`
`Review of the Safety and Efficacy of Exenatide Once Weekly for
`the Treatment of Type 2 Diabetes Mellitus
`
`Catherine E Murphy
`
`There is an epidemic of diabetes in the
`
`OBJECTIVE: To summarize and evaluate the available literature assessing the
`efficacy and safety of exenatide once weekly for the treatment of type 2 diabetes
`mellitus.
`DATA SOURCES: PubMed (1966-January 2012) and International Pharmaceutical
`Abstracts (1969-January 2012) were searched using the term exenatide once
`weekly. Abstracts presented at the European Association for the Study of Diabetes
`Annual Meeting in 2011 and reference citations from publications were reviewed for
`inclusion. Eli Lilly and Company and Amylin Pharmaceuticals were contacted for
`additional unpublished information.
`STUDY SELECTION AND DATA EXTRACTION: All English-language articles and
`abstracts were evaluated for inclusion. All randomized controlled trials were
`included in the review.
`DATA SYNTHESIS: The efficacy and safety of exenatide once weekly has been
`evaluated as initial monotherapy and as add-on therapy to metformin, sulfonylureas,
`and thiazolidinediones in patients with uncontrolled type 2 diabetes for up to 3 years.
`Results from 6 randomized, comparator-controlled studies in over 3000 patients
`indicate that treatment with exenatide once weekly results in significant glycemic
`improvements and weight loss. Gastrointestinal adverse effects and injection site
`reactions are common, but rarely lead to drug discontinuation.
`CONCLUSIONS: Exenatide once weekly holds promise as a convenient, efficacious,
`and well-tolerated antihyperglycemic agent for the treatment of type 2 diabetes.
`Studies evaluating outcomes such as cardiovascular events or all-cause mortality
`with exenatide once weekly are lacking.
`KEY WORDS: bydureon, exenatide extended-release, exenatide once weekly,
`type 2 diabetes mellitus.
`
`Ann Pharmacother 2012;46:812-21.
`
`Published Online, 5 Jun 2012, theannals.com, DOI 10.1345/aph.1Q722
`
`US, with the disease affecting an esti-
`mated 25 million people.1 Complications
`of diabetes contribute to excess morbidity
`and mortality and include cardiovascular
`disease, kidney disease, limb amputation,
`painful neuropathy, and blindness. Esti-
`mated total direct and indirect costs at-
`tributed to diabetes in the US were $174
`billion in 2007 and are likely more than
`that now given the increasing prevalence
`of the disease.2 The excess morbidity and
`mortality and staggering costs attributed to
`diabetes underline the need for effective
`prevention and treatment.
`Although recent studies have ques-
`tioned the clinical benefit of aggressive
`glycemic control, a hemoglobin A1c (A1C)
`less than 7.0% is an appropriate glycemic
`goal for most patients.3-5 This should be
`targeted with lifestyle modifications and
`pharmacologic therapies while avoiding
`severe hypoglycemia and adverse effects.
`Unfortunately, despite the availability of
`multiple effective antihyperglycemic ther-
`apies, almost half of patients with diabetes
`continue to have suboptimal glycemic
`control.6
`Modest weight loss can improve glycemic control and
`prevent progression or development of the disease, but most
`patients require pharmacologic therapy to manage hyper-
`glycemia.7,8 Guidelines for treatment of type 2 diabetes rec-
`ommend metformin as the initial therapy for most patients
`because of its efficacy, safety, tolerability, and low cost.9,10 Al-
`
`ternatives to metformin monotherapy include thiazolidine-
`diones, sulfonylureas, dipeptidyl peptidase- 4 (DPP- 4) in-
`hibitors, and glucagon-like peptide-1 (GLP-1) agonists. Ad-
`vantages of GLP-1 agonists include the low incidence of hy-
`poglycemia and associated weight loss; disadvantages
`include the need for administration via injection, frequent
`gastrointestinal adverse effects, and cost. Current guidelines
`do not recommend GLP-1 agonists as a first-line option, but
`they should be considered as monotherapy or adjunctive
`
`Author information provided at end of text.
`
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`
`therapy when hypoglycemia or weight loss is of particular
`concern, or when postprandial hyperglycemia is the primary
`target. These recommendations were published before the ap-
`proval of liraglutide, a long-acting GLP-1 agonist with a less
`pronounced effect on postprandial glucose (PPG) than exe-
`natide twice daily.11
`The first GLP-1 agonist, exenatide, was approved by the
`Food and Drug Administration (FDA) in 2005 as a twice-
`daily subcutaneous injection.12 Multiple studies have
`demonstrated that treatment with exenatide twice daily re-
`sults in reduction of both fasting and postprandial glucose
`and A1C lowering of up to 1.1% (generally about 0.6-
`0.9%).13-16 Advantages of exenatide twice daily include
`weight loss of approximately 2-3 kg and a low incidence
`of hypoglycemia. However, the usefulness of this formula-
`tion is limited by the high rate of gastrointestinal adverse
`effects, most notably nausea and vomiting, and the incon-
`venience of twice-daily injections that must be adminis-
`tered within 60 minutes before meals. Furthermore, the
`twice-daily formulation does not result in 24-hour
`glycemic coverage, and the rapid increase in exenatide
`serum concentrations after dosing may contribute to the
`high rate of gastrointestinal adverse effects.
`Liraglutide was approved in 2010.17 The longer half-life
`(12 hours vs 2.4 hours for exenatide) allows for once-daily
`dosing, which affords a more convenient administration
`schedule than exenatide twice daily. Additionally, liraglutide
`results in greater reductions in fasting plasma glucose (FPG)
`and an approximately 0.3% greater reduction in A1C than
`exenatide twice daily.11 Reductions in PPG after breakfast
`and dinner are greater with exenatide twice daily. Weight loss
`and overall tolerability with liraglutide appear to be similar to
`exenatide twice daily, while the incidence of hypoglycemia is
`significantly lower with the longer acting GLP-1 agonist.11
`The incidence of nausea and vomiting with liraglutide is
`slightly lower than that seen with exenatide twice daily, and
`gastrointestinal adverse effects tend to be more transient with
`liraglutide.
`The recent development of a once-weekly exenatide for-
`mulation may provide a more convenient antihyper-
`glycemic option for many patients with uncontrolled type
`2 diabetes. This new formulation uses biodegradable mi-
`crosphere technology to encapsulate the active drug and
`slowly release exenatide into the systemic circulation after
`subcutaneous injection. The result is therapeutic drug con-
`centrations over the entire dosing interval and a more grad-
`ual increase in serum drug concentrations after dosing,
`leading to the potential for greater efficacy and improved
`gastrointestinal tolerability. Exenatide extended-release
`was approved in January 2012 as an adjunct to diet and ex-
`ercise to improve glycemic control in patients with type 2
`diabetes. This article reviews and evaluates the evidence
`for the use of exenatide once weekly in the treatment of
`type 2 diabetes and its potential place in therapy.
`
`Data Sources
`
`A literature search was performed to identify English-
`language articles and abstracts using the search term exe-
`natide once weekly. Databases searched consisted of
`PubMed (1966-January 2012) and International Pharma-
`caceutical Abstracts (1969-January 2012). Abstracts present-
`ed at the European Association for the Study of Diabetes An-
`nual Meeting in 2011 were also reviewed for relevance and
`inclusion. Eli Lilly and Company and Amylin Pharmaceuti-
`cals, the developers of exenatide once weekly, were contact-
`ed for any available unpublished information and reference
`citations from recent publications were reviewed. All ran-
`domized controlled trials evaluating the efficacy and/or safety
`of exenatide once weekly were selected for review.
`
`Mechanism of Action
`
`GLP-1 is an incretin hormone secreted by enteroen-
`docrine cells in the intestinal mucosa in response to nutrient
`intake. The peptide has multiple glucoregulatory actions, in-
`cluding enhancement of glucose-dependent insulin secretion,
`suppression of glucagon secretion, inhibition of gastric emp-
`tying, and reduction in food intake.18 Exenatide is a GLP-1
`receptor agonist with an amino acid sequence similar to that
`of human GLP-1.12 Exenatide binds to and activates GLP-1
`receptors, resulting in pharmacologic actions similar to those
`of GLP-1 in the body and a reduction in both FPG and PPG
`concentrations.
`
`Pharmacokinetics
`
`Exenatide once weekly incorporates a technology with
`biodegradable polymer-based microspheres that encapsulate
`the active drug.19 When the formulation is injected subcuta-
`neously, the microspheres degrade slowly, allowing gradual,
`controlled release of the drug into the systemic circulation.
`The pharmacokinetics of exenatide once weekly have
`been assessed in 1 single-dose and 2 multiple-dose studies in
`patients with type 2 diabetes.20-22 Exenatide once weekly
`demonstrated a multiphasic concentration-time profile, with a
`small initial release of exenatide leading to an initial time to
`maximum concentration of 2.1-5.1 hours after a single dose,
`and 2 subsequent phases of drug release several weeks later,
`resulting in an overall mean time to maximum concentration
`of 6-7 weeks.22 Administration of exenatide 2 mg once week-
`ly resulted in minimal therapeutic concentrations (>50
`pg/mL) in approximately 2 weeks and steady-state concen-
`trations of approximately 300 pg/mL within 6-7 weeks.22
`Steady-state concentrations achieved with exenatide 2 mg
`once weekly are similar to the maximum concentration at-
`tained after a single dose of immediate-relase exenatide 10
`µg.22 The median half-life of exenatide once weekly is ap-
`proximately 2 weeks. After discontinuation, concentrations
`decrease to less than 50 pg/mL in approximately 6-7 weeks
`
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`CE Murphy
`
`and fall below the minimal detectable concentration (10
`pg/mL) within approximately 10 weeks. Other pharmacoki-
`netic data for exenatide once weekly would not be expected
`to differ from the twice-daily formulation. Exenatide twice
`daily is predominantly eliminated via glomerular filtration
`and has a mean apparent clearance of 9.1 L/h.12 Mean appar-
`ent volume of distribution is 28.3 L.
`
`Clinical Efficacy
`
`The clinical development of exenatide once weekly con-
`sisted of 6 pivotal Phase 3 studies comprising the DURA-
`TION program (Diabetes Therapy Utilization: Researching
`Changes in A1C, Weight and Other Factors Through Inter-
`vention with Exenatide Once Weekly). The DURATION
`studies evaluated the efficacy and safety of exenatide 2 mg
`once weekly in patients with uncontrolled type 2 diabetes
`compared to exenatide twice daily or other antihyper-
`glycemics (Table 1).21,23-27 All of the studies were spon-
`sored by Eli Lilly and Amylin Pharmaceuticals, and study
`sponsors were involved in the design, protocol develop-
`ment, collection, review, interpretation, and analysis of
`data, as well as preparation of the study manuscripts.
`Background therapy in the DURATION studies consisted
`of diet and exercise alone, or 1 or more oral antihyper-
`glycemics (metformin, a sulfonylurea, or pioglitazone). In-
`clusion criteria included baseline A1C of 7.1-11.0%, stable
`body weight, and body mass index (BMI) of 25-45 kg/m2.
`Exclusion criteria varied depending on the study. The prima-
`ry efficacy end point for each study was change in A1C from
`baseline to the end of the study; secondary end points includ-
`ed proportion of patients achieving a target A1C (<7.0% or
`<6.5%), change in FPG, and change in body weight. Each
`
`study also reported the incidence of treatment-emergent ad-
`verse events and changes in blood pressure and lipid levels.
`None of the DURATION studies reported or were powered
`to compare differences in clinical outcomes such as cardio-
`vascular events or all-cause mortality. Baseline characteristics
`of patients included in the DURATION clinical trial program
`were similar among the studies and included mean A1C 8.3-
`8.6%, FPG 164-178 mg/dL, and BMI 31-35 kg/m2. Individu-
`al results of each DURATION study are summarized below
`and in Table 2.21,23-27
`
`EXENATIDE ONCE WEEKLY COMPARED TO EXENATIDE
`TWICE DAILY
`
`DURATION-121 and DURATION-523 were randomized,
`controlled, open-label, noninferiority studies that compared
`the efficacy and safety of exenatide once weekly to that of
`exenatide 10 µg twice daily as initial monotherapy or add-
`on therapy over 24-30 weeks. Participants were being
`treated with diet and exercise alone or background oral an-
`tihyperglycemic therapy with up to 2 medications (any
`combination of metformin, a sulfonylurea, and/or a thiazo-
`lidinedione). Although both are described as noninferiority
`studies, superiority analyses were conducted for all out-
`comes. All safety analyses were reported for the intent-to-
`treat (ITT) population. Although most efficacy results were
`reported for the ITT population, DURATION-1 reported
`some secondary glycemic end points only for the modified
`per-protocol population (defined as participants who com-
`pleted study procedures until no more than 4 weeks re-
`mained until the end of the study).
`Results of DURATION-1 demonstrated significantly
`greater reductions in A1C and a significantly greater propor-
`
`Study
`
`Comparator
`
`Design
`
`Duration
`
`Table 1. Summary of Pivotal Studies
`
`30 weeks (plus open-
`ended extension phase)
`
`26 weeks (+ 26-week
`extension phase)
`
`26 weeks (+ 58-week
`extension phase)
`26 weeks
`
`Pts,
`N
`
`Background
`Treatment
`
`295 Diet and exercise, metformin,
`sulfonylurea, thiazolidinedione, or
`combination of 2
`491 Metformin
`
`456 Metformin ± sulfonylurea
`
`820 Diet and exercise
`
`DURATION Exenatide 10 µg twice daily
`121
`
`DURATION Sitagliptin 100 mg once daily,
`224
`pioglitazone 45 mg once daily
`
`Randomized, open-label,
`non-inferiority, comparator-
`controlled
`Randomized, double-blind,
`double-dummy,
`comparator-controlled
`Randomized, open-label,
`DURATION Insulin glargine
`326
`comparator-controlled
`DURATION Metformin up to 2500 mg once Randomized, double-blind,
`425
`daily, sitagliptin 100 mg once
`double-dummy, comparator-
`daily, pioglitazone 45 mg once
`controlled
`daily
`DURATION Exenatide 10 µg twice daily
`523
`
`DURATION Liraglutide 1.8 mg once daily
`627
`
`Randomized, open-label,
`noninferiority, comparator-
`controlled
`Randomized, open-label,
`comparator-controlled
`
`24 weeks
`
`26 weeks
`
`252 Diet and exercise, metformin,
`sulfonylurea, thiazolidinedione, or
`combination of 2
`911 Metformin, sulfonylurea, sulfonylurea
`± sulfonylurea /thiazolidinedione
`
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`tion of patients achieving an A1C goal of less than 7% at the
`study’s end with exenatide once weekly compared to exe-
`natide twice daily.21 The proportion of patients achieving the
`A1C goal was reported only for the modified per-protocol
`population, thereby likely overestimating the real-world ef-
`fectiveness of exenatide for this outcome. Treatment with ex-
`enatide once weekly resulted in significantly greater im-
`provements in FPG (– 41 vs –25 mg/dL; p < 0.0001), while
`improvements in PPG were greater with the twice-daily for-
`mulation (–124 vs –95 mg/dL; p = 0.0124). Reductions in
`body weight were similar in both treatment groups.
`Consistent with results from DURATION-1, DURA-
`TION-5 also demonstrated significantly greater reductions
`in A1C and FPG (–35 vs –12 mg/dL; p = 0.0008) and a
`greater proportion of patients achieving A1C goal with ex-
`enatide once weekly compared to exenatide twice daily.23
`DURATION-5 did not report results for PPG. Weight loss
`was similar between the study groups, although numerical-
`ly less than that observed in DURATION-1. This is likely a
`result of the shorter duration of treatment with the study
`drug in DURATION-5.
`
`Exenatide Once Weekly for Type 2 Diabetes
`
`Strengths of both DURATION-1 and DURATION-5 in-
`cluded high completion rates (>80%), few patients lost to
`follow-up, and the randomized controlled design. Conceal-
`ment of allocation was described in DURATION-5, but
`not in DURATION-1. A major weakness of both studies
`was the unblinded open-label design.
`
`COMPARED TO ORAL ANTIHYPERGLYCEMICS
`
`DURATION-2 was a 26-week randomized, double-blind,
`double-dummy study that compared the safety, efficacy, and
`tolerability of exenatide once weekly, sitagliptin 100 mg dai-
`ly, and pioglitazone 45 mg daily in 491 patients with type 2
`diabetes inadequately controlled with metformin monothera-
`py.24 All results were reported for the ITT population. Exe-
`natide once weekly added to metformin resulted in signifi-
`cantly greater reductions in A1C at 26 weeks compared to
`sitagliptin or pioglitazone. Reductions in FPG with exenatide
`once weekly (–32 mg/dL) were significantly greater than
`those achieved with sitagliptin (–16 mg/dL; p = 0.0038 vs ex-
`enatide) but not pioglitazone (–27 mg/dL; p = 0.3729 vs exe-
`
`Table 2. Results from Pivotal Studies
`
`Study
`
`Treatment
`
`Proportion
`Achieving
`A1C <7%
`
`DURATION
`121
`
`DURATION
`224,c
`
`DURATION
`326
`
`DURATION
`425
`
`DURATION
`523
`
`DURATION
`627
`
`Exenatide once
`weekly
`Exenatide twice
`daily
`Exenatide once
`weekly
`Sitagliptin
`Pioglitazone
`Exenatide once
`weekly
`Insulin glargine
`Exenatide once
`weekly
`Metformin
`Sitagliptin
`Pioglitazone
`Exenatide once
`weekly
`Exenatide twice
`daily
`Exenatide once
`weekly
`Liraglutide
`
`77
`
`61b
`
`60
`
`48b
`63
`
`55
`43b
`61
`58
`
`30b
`
`52
`
`60b
`
`A1C,
`%
`
`–1.9a
`
`–1.5a,b
`
`–1.5a
`
`–0.9a,b
`–1.2a,b
`–1.5a
`
`–1.3a,b
`–1.5a
`
`–1.5a
`–1.2a,b
`–1.6a
`–1.6a
`
`–0.9a,b
`
`–1.3a
`
`TC,
`%
`
`–7a
`
`–2
`
`–2a
`
`–1
`
`–8a
`
`0b
`
`Weight,
`kg
`
`–3.7a
`
`–3.6a
`
`–2.3a
`
`–0.8a,b
`+2.8a,b
`–2.6a
`
`+1.4a,b
`–2.0
`
`–2.0
`–0.8b
`+1.5b
`–2.3a
`
`–1.4a
`
`–2.7a
`
`–1.5a,b
`
`–3.6a,b
`
`Changes
`
`LDL-C,
`%
`
`HDL-C,
`%
`
`–5a
`
`+1
`
`–2
`
`+1
`
`–6a
`
`+2b
`
`–2
`
`–3a
`
`0
`
`+1
`
`0
`
`+3
`
`TG,
`%
`
`–15
`
`–11
`
`SBP,
`mm Hg
`
`–4.7a
`
`–3.4
`
`DBP,
`mm Hg
`
`–1.7a
`
`–1.7a
`
`–4
`
`–11
`
`–6
`
`–1
`
`–3a
`
`–1
`–1.3
`
`–1.8
`–1.7
`–2.9a
`
`–1.2
`
`–2.5
`
`–3.5
`
`–1
`
`–1
`
`–2.5
`+0.2
`
`–0.1
`
`–0.5
`
`–0.5
`
`A1C = hemoglobin A1c; DBP = diastolic blood pressure; HDL-C = high-density lipoprotein cholesterol; LDL-C = low-density lipoprotein cholesterol; SBP =
`systolic blood pressure; TC = total cholesterol; TG = triglycerides.
`ap < 0.05 versus baseline.
`bp < 0.05 versus exenatide once weekly.
`cAlthough DURATION-2 evaluated the effects of the study drugs on lipids and blood pressure, numeric values were not reported in the article.
`
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`
`natide). Weight loss at 26 weeks was also significantly
`greater with exenatide once weekly compared to sitagliptin
`and pioglitazone. A methodologic strength of DURATION-2
`was its double-blind, double-dummy design. In addition,
`treatment allocation was concealed and performed via a cen-
`tral site.
`DURATION- 4 was a randomized, controlled, double-
`blind 26-week study that compared the efficacy and safety of
`exenatide once weekly, metformin 2500 mg/day, pioglita-
`zone 45 mg/day, or sitagliptin 100 mg/day as initial
`monotherapy in 820 patients with uncontrolled type 2 dia-
`betes.25 All results were reported for the ITT population.
`Treatment with exenatide once weekly resulted in a similar
`approximate 1.5% reduction in A1C compared to metformin
`or pioglitazone and a significantly greater reduction than that
`achieved with sitagliptin. Reductions in FPG with exenatide
`once weekly (– 40.5 mg/dL) were similar to those with met-
`formin (–35.7 mg/dL) and pioglitazone (– 46.3 mg/dL) and
`significantly greater than that with sitagliptin (–20.4 mg/dL; p
`< 0.001). A similar proportion of patients in each treatment
`group achieved an A1C less than 7.0%, with the exception of
`sitagliptin, which was less effective with regard to this end
`point. Both exenatide once weekly and metformin resulted in
`a similar mean weight loss of 2 kg. Treatment with pioglita-
`zone resulted in weight gain, consistent with previous studies.
`Strengths of DURATION-4 included the randomized, dou-
`ble-blind study design, concealment of allocation via a cen-
`tral site, and high completion rates (approximately 85%).
`
`COMPARED TO INSULIN GLARGINE
`
`DURATION-3 was an open-label, randomized, 26-
`week study comparing exenatide once weekly with insulin
`glargine in 456 patients with type 2 diabetes suboptimally
`controlled with metformin monotherapy or metformin and
`sulfonylurea combination therapy.26 Patients were random-
`ized to receive exenatide once weekly or insulin glargine
`added to their background therapy. Insulin glargine was
`initiated at 10 units daily and titrated up according to FPG.
`Analyses were done for the ITT population. Reduction in
`A1C at 26 weeks was, on average, 0.2% greater for pa-
`tients receiving exenatide once weekly compared to those
`receiving insulin glargine (p < 0.05). Mean weight loss at
`week 26 with exenatide once weekly was similar to that in
`previously described studies, while insulin glargine was as-
`sociated with weight gain. Reductions in FPG were greater
`with insulin glargine (–50 vs –38 mg/dL; p = 0.001), while
`reductions in PPG after morning and evening meals were
`greater with exenatide once weekly (numeric results not re-
`ported; p < 0.05). The primary methodologic weakness of
`DURATION-3 was its unblinded, open-label design. Loss to
`follow-up was very low, and over 90% of patients random-
`ized to treatment completed the study. However, more pa-
`tients receiving exenatide once weekly withdrew (10.3% vs
`
`6.3%). Although patients and investigators were asked to ad-
`here to titration targets with insulin glargine, no assessment or
`enforcement of such titration was done. Of note, sulfonylurea
`background therapy was being used by approximately 30%
`of patients in each treatment arm. Continuation of a sulfony-
`lurea with initiation of basal insulin may be somewhat con-
`troversial due to the potential for additive weight gain with
`the combination and possible minimal additional glycemic
`benefit. Concensus guidelines from the American Diabetes
`Association do not recommend the combination of any in-
`sulin with a sulfonylurea.10 However, the combination of
`basal insulin and a sulfonylurea is not inconsistent with
`guidelines from the American Association of Clinical En-
`docrinologists, whose algorithm for glycemic control speci-
`fies that insulin secretagogues must be discontinued on initia-
`tion of prandial insulin, but not basal insulin alone.9 The
`guidelines do, however, acknowledge the additive risk of
`weight gain and fluid retention with the combination, and
`certainly this likely contributed to the weight gain in the in-
`sulin glargine arm in DURATION-3.
`
`COMPARED TO LIRAGLUTIDE
`
`DURATION-6 was a 26-week, open-label, randomized,
`noninferiority study comparing exenatide once weekly to
`liraglutide 1.8 mg daily as add-on therapy to metformin, a
`sulfonylurea, and/or pioglitazone in 911 patients with un-
`controlled type 2 diabetes.27 Preliminary results indicated
`that A1C reduction was 0.2% greater in patients taking li-
`raglutide than exenatide and did not meet the prespecified
`noninferiority criteria. Liraglutide-treated patients lost sig-
`nificantly more weight and a greater proportion achieved
`an A1C less than 7%. Of note, the reductions in A1C with
`exenatide once weekly in this study were of lower magni-
`tude than those seen in the previous DURATION studies,
`and full results of this study have yet to be published in a
`peer-reviewed journal and so should be interpreted with
`caution. A detailed description of study methods is not
`available and therefore cannot be assessed for validity.
`
`Long-Term Efficacy
`
`Continuation phase results for up to 2 years for DURA-
`TION-1, DURATION-2, and DURATION-3 have been pub-
`lished.28-32 Analyses of these continuation phase data indicate
`that improvements in glycemic parameters and weight loss
`are maintained over the long term. At 2 years, mean change
`from baseline in A1C was –1.7% and in FPG – 40.1 mg/dL;
`60% of patients maintained an A1C less than 7%.29 Although
`a small increase in weight was observed after 26 weeks,
`weight loss was maintained and at 2 years was approximately
`a 2-kg reduction from baseline. Results from 3-year data are
`preliminary, but suggest that improvements in glycemic con-
`trol and weight loss are maintained at this timepoint.31
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`Effects on Cardiovascular Parameters
`
`None of the DURATION studies assessed the effect of
`exenatide on cardiovascular morbidity or mortality. Vari-
`ous surrogate cardiovascular markers have been assessed.
`Although several studies reported a small but significant
`increase in mean heart rate of about 4 beats/min,23,26 most
`other cardiovascular measures either improved or re-
`mained stable during treatment with exenatide once week-
`ly. Improvements, although of questionable clinical signifi-
`cance, were noted in systolic blood pressure (~3-mm Hg
`reduction) in several studies. At 2 years, blood pressure ef-
`fects were attenuated, but still improved from baseline.30
`Mean total cholesterol and low-density lipoprotein choles-
`terol levels and triglycerides significantly decreased with exe-
`natide once-weekly treatment, although reductions were
`small and likely of little clinical significance. Effects on high-
`density lipoprotein cholesterol were not consistent, with some
`studies showing a slight decrease21 and others finding a sig-
`nificant increase.24,25,30 Several studies noted significant (p <
`0.05) improvements from baseline in other cardiovascular
`markers as well, including C-reactive protein,24-26 adiponec-
`tin,24 and B-type natriuretic peptide.24
`Preliminary results of analyses from 148 patients in DU-
`RATION-1 found no clinically significant effect of exe-
`natide once weekly on QTc interval over 30 weeks of treat-
`ment, including in patients with renal dysfunction.33 Any
`changes observed in QTc interval were not accentuated in
`patients with the highest exenatide concentrations.
`
`Adverse Effects
`
`The safety and tolerability of treatment with exenatide
`once weekly for up to 2 years have been reported. Table
`321,23-27 summarizes the most common treatment-emergent
`adverse events reported in each DURATION study. The
`overall withdrawal rate resulting from adverse events in
`patients taking exenatide once weekly was low (4.9%) and
`most commonly due to nausea.12 Of note however, with-
`drawal rates associated with adverse events and overall
`withdrawal rates were numerically higher with exenatide
`once weekly than with the comparator drug in several stud-
`ies (Table 3). The most common adverse effects reported
`in clinical studies with exenatide once weekly were gas-
`trointestinal (most frequently nausea) and injection site reac-
`tions, most commonly injection site nodules. Generally, gas-
`trointestinal adverse effects reported were described as mild
`to moderate and improved with duration of therapy. Pooled
`analyses of completed trials (DURATION-1, -2, -3, and -5)
`found an overall incidence of nausea of 9% with exenatide
`once-weekly monotherapy, with higher rates in patients on
`concomitant metformin therapy.34 Discontinuation rates asso-
`ciated with nausea were very low. Gastrointestinal adverse
`effects were more common with exenatide twice daily than
`
`Exenatide Once Weekly for Type 2 Diabetes
`
`with exenatide once weekly, while injection site reactions
`tended to be more common with the once-weekly formula-
`tion.
`There was one reported case of major hypoglycemia
`(defined as blood glucose <54 mg/dL associated with loss of
`consciousness or requiring third-party assistance) with exe-
`natide once weekly.26 This occurred in a patient taking met-
`formin and exenatide once weekly, was not associated with
`loss of consciousness, and resolved with oral carbohydrate
`administration. The incidence of minor hypoglycemia was
`generally low, occurring in about 7% of patients taking exe-
`natide once-weekly monotherapy.34 The highest incidence of
`hypoglycemia occurred in patients taking a concomitant sul-
`fonylurea.
`
`Drug Interactions
`
`The potential for drug interactions with exenatide once
`weekly has not been evaluated extensively. Exenatide twice
`daily has the potential to reduce the extent and rate of absorp-
`tion of other drugs because of its effect on slowing gastric
`emptying, and exenatide once weekly would not be expected
`to differ in this regard.12 There is limited evidence that the
`long-acting formulation may have less inhibitory effect on
`gastric emptying than exenatide twice daily.21 The potential
`for drug interactions may be of particular concern with orally
`administered medications that have a narrow therapeutic in-
`dex and/or are dependent on threshold concentrations for effi-
`cacy.
`Patients taking concomitant antihyperglycemic therapy,
`particularly sulfonylureas, are at increased risk for hypo-
`glycemia with exenatide once weekly. Reduction of the
`sulfonylurea dose on initiation of exenatide once weekly
`should be considered.12
`
`Precautions and Contraindications
`
`Exenatide once weekly is contraindicated in patients
`with a personal or family history of medullary thyroid car-
`cinoma, due to an increased incidence of thyroid cell tu-
`mors seen in animal studies. Exenatide once weekly
`should be avoided in patients with severe renal impairment
`and should be used with caution in patients with moderate
`renal dysfunction (creatinine clearance 30-50 mL/min) be-
`cause of the potential for drug accumulation and worsened
`renal function from hypovolemia due to drug-induced nau-
`sea and vomiting.12
`Exenatide is not recommended in patients with severe
`gastrointestinal disease or gastroparesis. Exenatide has
`been associated with acute pancreatitis, including fatal cas-
`es,35,36 and should generally be avoided in patients with a
`history of pancreatitis. There have been 2 cases of pancre-
`atitis reported in clinical studies with exenatide once week-
`ly, both of which resolved.23,26
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`Dosage and Administration
`
`Exenatide once weekly is given as a 2-mg subcutaneous
`injection every 7 days. Unlike the twice-daily formulation,
`the dose of exenatide once weekly does not require titra-
`tion and can be administered without regard to meals.
`
`Discussion
`
`Results of the DURATION studies demonstrate signifi-
`cant and consistent improvements in glycemic control with
`exenatide once weekly, regardless of background antihy-
`perglycemic therapy. A1C reductions were generally about
`1.5% after 6 months of treatment. In comparative studies,
`A1C reductions with exenatide once weekly were greater
`than those achieved with exenatide twice daily, sitagliptin,
`or insulin glargine, and were comparable to those of met-
`formin and pioglitazone. Only liraglutide demonstrated
`significantly greater A1C reduction. Results from as long
`as 3 years of treatment indicate that improvements in
`glycemic control are generally sustained, with some mod-
`est attenuation over the longer term.28,29,31,32
`Although the low discontinuation rates associated with
`adverse events in clinical studies with exenatide once
`
`weekly suggest reasonable tolerability, withdrawal rates were
`higher with exenatide once weekly than with the comparator
`in several studies. Gastrointestinal adverse effects such as
`nausea and vomiting and injection site reactions were com-
`mon, although these adverse effects appeared to diminish
`over time. An advantage of incretin-based agents such as ex-
`enatide is the low rate of hypoglycemia, and this was con-
`firmed in the DURATION studies. Hypoglycemia that oc-
`curred was predominantly minor, and the majority of cases
`occurred in patients taking background sulfonylurea thera-
`py. Given the low rate of hypoglycemia with exenatide
`once weekly, this agent may be preferred over insulin or
`sulfonylureas in patients for whom hypoglycemia is of par-
`ticular concern, such as those with inconsistent eating
`habits or with hypoglycemic unawareness.
`Many patients with type 2 diabetes are significantly
`overweight, a factor that can contribute to insulin resis-
`tance and have adverse consequences on other health con-
`ditions and general quality of life. A therapeutic advantage
`of GLP-1 agonists is the beneficial side effect of weight
`loss. Weight loss in clinical studies with exenatide once
`weekly was approximately 2-3 kg, similar to that achieved
`with exenatide twice daily or metformin. Although weight
`loss tended to be greater in patients wit