`
`T R E A T M E N T S
`
`Long-Acting Glucagon-Like Peptide 1
`Receptor Agonists
`A review of their efficacy and tolerability
`
`ALAN J. GARBER, MD, PHD
`
`T argeting the incretin system has be-
`
`come an important therapeutic ap-
`proach for treating type 2 diabetes.
`Two drug classes have been developed:
`glucagon-like peptide (GLP)-1 receptor
`agonists and dipeptidyl peptidase 4
`(DPP-4) inhibitors. Clinical data have
`revealed that these therapies improve gly-
`cemic control while reducing body weight
`(GLP-1 receptor agonists, specifically) and
`systolic blood pressure (SBP) in patients
`with type 2 diabetes. Furthermore, in-
`cidence of hypoglycemia is relatively low
`with these treatments (except when used
`in combination with a sulfonylurea) be-
`cause of their glucose-dependent mecha-
`nism of action. There are currently two
`GLP-1 receptor agonists available (exena-
`tide and liraglutide), with several more
`currently being developed. This review
`considers the efficacy and safety of both
`the short- and long-acting GLP-1 receptor
`agonists. Head-to-head clinical trial data
`suggest that long-acting GLP-1 receptor
`agonists produce superior glycemic con-
`trol when compared with their short-
`acting counterparts. Furthermore, these
`long-acting GLP-1 receptor agonists were
`generally well tolerated, with transient
`nausea being the most frequently reported
`adverse effect.
`Careful consideration should be given
`to the selection of therapies for managing
`type 2 diabetes. In particular, antidiabetic
`agents that offer improved glycemic con-
`trol without increasing cardiovascular risk
`
`factors or rates of hypoglycemia are war-
`ranted. At present, many available treat-
`ments for type 2 diabetes fail to maintain
`glycemic control in the longer term be-
`cause of gradual disease progression as
`b-cell function declines. Where sulfony-
`lureas or thiazolidinediones (common
`oral antidiabetic drugs) are used, the risk
`of hypoglycemia and weight gain can in-
`crease (1,2). The development of new
`therapies for the treatment of type 2 dia-
`betes that, in addition to maintaining gly-
`cemic control, could reduce body weight
`and hypoglycemia risk (3,4), may help
`with patient management. Indeed, guide-
`lines have been developed that support
`the consensus that blood pressure, weight
`reduction, and avoidance of hypoglycemic
`events should be targeted in type 2 dia-
`betes management alongside glycemic tar-
`gets. For example, the American Diabetes
`Association (ADA) defines multiple goals
`of therapy that include A1C ,7.0% and
`SBP ,130 mmHg and no weight gain
`(or, in the case of obese subjects, weight
`loss) (5). In particular, incretin-based
`therapies (GLP-1 receptor agonists, spe-
`cifically) can help meet these new tar-
`gets by offering weight reduction,
`blood pressure reduction, and reduced
`hypoglycemia in addition to glycemic
`control.
`
`WHAT IS GLP-1?—The incretin
`effect, responsible for 50–70% of total
`insulin secretion after oral glucose
`
`c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c c
`
`From the Molecular and Cellular Biology Division of Diabetes, Endocrinology and Metabolism, Baylor College
`of Medicine, Houston, Texas.
`Corresponding author: Alan J. Garber, agarber@bcm.tmc.edu.
`This publication is based on the presentations at the 3rd World Congress on Controversies to Consensus in
`Diabetes, Obesity and Hypertension (CODHy). The Congress and the publication of this supplement were
`made possible in part by unrestricted educational grants from AstraZeneca, Boehringer Ingelheim, Bristol-
`Myers Squibb, Daiichi Sankyo, Eli Lilly, Ethicon Endo-Surgery, Generex Biotechnology, F. Hoffmann-La
`Roche, Janssen-Cilag, Johnson & Johnson, Novo Nordisk, Medtronic, and Pfizer.
`DOI: 10.2337/dc11-s231
`The article contains Supplementary Data online at http://care.diabetesjournals.org/lookup/suppl/doi:10.2337/
`dc11-s231/-/DC1.
`© 2011 by the American Diabetes Association. Readers may use this article as long as the work is properly
`cited, the use is educational and not for profit, and the work is not altered. See http://creativecommons.org/
`licenses/by-nc-nd/3.0/ for details.
`
`administration, is defined as the differ-
`ence in insulin secretory response from
`an oral glucose load compared with intra-
`venous
`glucose
`administration (6)
`(Supplementary Fig. 1).
`There are two naturally occurring
`incretin hormones that play a role in the
`maintenance of glycemic control: glucose-
`dependent insulinotropic polypeptide
`and GLP-1, both of which have a short
`half-life because of their rapid inactivation
`by DPP-4 (7). In patients with type 2 di-
`abetes, the incretin effect is reduced or, in
`some cases, absent (8). In particular, the
`insulinoptropic action of glucose-depen-
`dent insulinotropic polypeptide is lost in
`patients with type 2 diabetes. However, it
`has been shown that, after administration
`of pharmacological levels of GLP-1, the in-
`sulin secretory function can be restored in
`this population (9), and thus GLP-1 has
`become an important target for research
`into new therapies for type 2 diabetes.
`GLP-1 has multiple physiological ef-
`fects that make it an attractive candidate
`for type 2 diabetes therapy. It increases
`insulin secretion while inhibiting gluca-
`gon release, but only when glucose levels
`are elevated (6,10), thus offering the po-
`tential to lower plasma glucose while re-
`ducing the likelihood of hypoglycemia.
`Furthermore, gastric emptying is delayed
`(10) and food intake is decreased after
`GLP-1 administration. Indeed, in a 6-
`week study investigating continuous
`GLP-1 infusion, patients with type 2 di-
`abetes achieved a significant weight loss
`of 1.9 kg and a reduction in appetite from
`baseline compared with patients receiving
`placebo, where there was no significant
`change in weight or appetite (11). Preclini-
`cal studies reveal other potential benefits
`of GLP-1 receptor agonist treatment in
`individuals with type 2 diabetes, which
`include the promotion of b-cell prolifera-
`tion (12) and reduced b-cell apoptosis
`(13). These preclinical results indicate
`that GLP-1 could be beneficial in treating
`patients with type 2 diabetes. However,
`because native GLP-1 is rapidly inactivated
`and degraded by the enzyme DPP-4 and
`has a very short half-life of 1.5 min (14), to
`achieve the clinical potential for native
`
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`
`Long-acting GLP-1s: efficacy and tolerability
`
`GLP-1, patients would require 24-h ad-
`ministration of native GLP-1 (15). Be-
`cause this is impractical as a therapeutic
`option for type 2 diabetes, it was neces-
`sary to develop longer-acting derivatives
`of GLP-1.
`
`DEVELOPMENT OF DPP-4–
`RESISTANT GLP-1 RECEPTOR
`AGONISTS—Two classes of incretin-
`based therapy have been developed to
`overcome the clinical limitations of na-
`tive GLP-1: GLP-1 receptor agonists (e.g.,
`liraglutide and exenatide), which exhibit
`increased resistance to DPP-4 degradation
`and thus provide pharmacological levels
`of GLP-1, and DPP-4 inhibitors (e.g., sita-
`gliptin, vildagliptin, saxagliptin), which
`reduce endogenous GLP-1 degradation,
`thereby providing physiological levels of
`GLP-1. In this review, we focus on the
`GLP-1 receptor agonist class of incretin-
`based therapies. The efficacy and tolera-
`bility of the DPP-4 inhibitors have been
`reviewed elsewhere (16). Two GLP-1 recep-
`tor agonists are licensed at present in Eu-
`rope, the U.S., and Japan: exenatide (Byetta,
`Eli Lilly) (17) and liraglutide (Victoza, Novo
`Nordisk) (18). For the purposes of this re-
`view, we refer to “short-acting” GLP-1 re-
`ceptor agonists as those agents having
`duration of action of ,24 h and “long-
`acting” as those agents with duration of
`action .24 h (Table 1).
`
`OVERVIEW OF LICENSED
`GLP-1 RECEPTOR AGONISTS
`
`Exenatide
`Exenatide, an exendin-4 mimetic with
`53% sequence identity to native GLP-1,
`is currently approved for the treatment of
`type 2 diabetes as monotherapy (in the
`U.S.) (19) and in combination with met-
`formin 6 sulfonylurea (17). Because of
`its half-life of 2.4 h, exenatide is recom-
`mended for twice-daily dosing.
`Clinical trial results have demon-
`strated that exenatide, when used in com-
`bination with selected oral antidiabetic
`drugs, effectively reduces A1C by 20.4
`
`to 21.5% in patients with type 2 diabetes
`inadequately controlled on metformin
`with or without a sulfonylurea (20–24).
`Across these studies, body weight was
`seen to decrease in a dose-dependent
`manner; treatment with 10 mg exenatide,
`as an add-on to metformin, resulted in the
`greatest weight loss (22.8 kg) in patients
`previously treated with metformin alone
`(21). Exenatide was generally well toler-
`ated, with mild-to-moderate gastrointesti-
`nal effects being the most common
`adverse effect (20–23). The number of pa-
`tients experiencing nausea peaked during
`the initial weeks of treatment (0–8 weeks)
`but decreased thereafter. Rates of hypogly-
`cemia were relatively low in these studies,
`although frequency of hypoglycemia was
`increased when exenatide was used in
`combination with a sulfonylurea (20). In-
`deed, the summary of product character-
`istics for exenatide states that when
`exenatide is used in combination with a
`sulfonylurea, consideration should be
`given to reducing the sulfonylurea dose
`to reduce the risk of hypoglycemia (17).
`
`Liraglutide
`Liraglutide is a GLP-1 analog that shares
`97% sequence identity to native GLP-1
`(25). The addition of a C16 fatty acid side
`chain enables once-daily dosing of lira-
`glutide by prolonging its duration of ac-
`tion to over 24 h. This protraction is
`achieved through reversible binding to al-
`bumin and increased stability through
`heptamer formation mediated by the fatty
`acid side chain (26).
`The safety and efficacy of liraglutide
`have been well detailed in the phase 3
`Liraglutide Effect and Action in Diabetes
`(LEAD) trials (27–32). Data from the
`LEAD trials have demonstrated that lira-
`glutide effectively improves glycemic
`control (up to a 1.5% decrease in A1C)
`in individuals with type 2 diabetes, when
`used as monotherapy or in combination
`with one or more selected oral anti-
`diabetic drugs. Across the trials, body
`weight was seen to decrease; the largest
`weight loss resulted from treatment with
`
`Table 1—Short- and long-acting GLP-1 receptor agonists
`
`Short-acting ,24 h
`Twice daily
`
`Long-acting $24 h
`
`Once daily
`
`Once weekly
`
`Exenatide (launched)
`
`Liraglutide (launched)
`
`Exenatide LAR (phase 3)
`Taspoglutide (phase 3)
`Albiglutide (phase 3)
`LY2189265 (phase 2)
`
`liraglutide in combination with metfor-
`min 6 sulfonylurea (23.24 kg with 1.8
`mg liraglutide). Reductions in SBP were
`also observed across the trials (mean de-
`crease 22.1 to 26.7 mmHg) (27–32).
`Liraglutide was generally well toler-
`ated, with only transient nausea experi-
`enced toward the beginning of
`the
`studies. The rate of minor hypoglycemia
`was very low in these trials (incidence
`ranged from 0.03 to 0.6 events/patient/
`year with the different treatment groups
`[excluding those using liraglutide in com-
`bination with a sulfonylurea]). However,
`as seen in the exenatide trials, frequency
`of hypoglycemia increased slightly when
`liraglutide was used in combination with
`a sulfonylurea (incidence of major hypo-
`glycemia: 0.056 events/patient/year; minor
`hypoglycemia: 1.2 events/patient/year with
`1.8 mg liraglutide in combination with
`metformin and a sulfonylurea).
`
`OVERVIEW OF GLP-1
`RECEPTOR AGONISTS IN
`DEVELOPMENT—In addition to lir-
`aglutide and exenatide, there are several
`once-weekly GLP-1 receptor agonists in
`development: exenatide long-acting release
`(LAR) (Eli Lilly/Amylin), taspoglutide
`(Roche), albiglutide (GlaxoSmithKline),
`and LY2189265 (Eli Lilly) (Supplementary
`Table 1).
`At the time of writing, Roche had
`suspended the development of taspoglu-
`tide, currently in phase 3 trials, because of
`the high discontinuation rates as a result
`of gastrointestinal tolerability and serious
`hypersensitivity reactions (33).
`
`LONG- VERSUS SHORT-
`ACTING GLP-1 RECEPTOR
`AGONISTS: EFFICACY AND
`TOLERABILITY—A number of phase
`3 head-to-head trials have been conducted
`investigating the efficacy and tolerability
`of long- versus short-acting GLP-1 receptor
`agonists, results of which are briefly de-
`scribed here.
`
`Once-daily liraglutide versus
`twice-daily exenatide
`The efficacy and tolerability of once-daily
`liraglutide were compared with twice-
`daily exenatide in a phase 3 randomized
`head-to-head trial over 26 weeks involv-
`ing 464 patients (32). Results from this
`trial revealed that liraglutide provided a
`significantly greater reduction in mean
`A1C compared with exenatide (21.12 vs.
`20.79%; P , 0.0001) (Supplementary
`Fig. 2). As a result, a greater proportion of
`
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`
`patients with type 2 diabetes reached the
`ADA A1C target (#7.0%) (3) with liraglu-
`tide compared with exenatide (54 vs. 43%;
`P = 0.0015) (32). In addition, fasting
`plasma glucose significantly decreased
`with liraglutide treatment (21.61 mmol/L
`with liraglutide vs. 20.60 mmol/L with ex-
`enatide; P , 0.0001).
`The effects on body weight were
`similar with both liraglutide and exena-
`tide (23.24 vs. 22.87 kg, respectively),
`with a similar proportion of patients los-
`ing weight in both treatment groups (78%
`with liraglutide vs. 76% with exenatide)
`(32). Both drugs were well tolerated, with
`only mild-to-moderate side effects ob-
`served. Nausea was reported as the most
`common adverse effect with both treat-
`ments, although it was less frequent and
`less persistent with liraglutide. Further
`benefits of liraglutide treatment included
`a reduced number of hypoglycemic events
`and higher overall treatment satisfaction.
`A 14-week LEAD-6 extension study
`was also completed, in which patients,
`already randomized to liraglutide, stayed
`on liraglutide, and those on exenatide
`switched to once-daily liraglutide (34).
`Individuals switching from exenatide to
`liraglutide achieved an additional reduc-
`tion in A1C of 20.3%, from 7.2% at week
`26 to 6.9% at week 40 (Supplementary
`Fig. 2). Further reductions in fasting
`plasma glucose (20.9 mmol/L), body
`(20.9 kg), and SBP (23.8
`weight
`mmHg) were also seen after the switch
`to liraglutide. Patients switched from ex-
`enatide to liraglutide also experienced a
`reduction in rates of hypoglycemia from
`2.6 episodes/patient-year at week 26 to
`1.3 episodes/patient-year at week 40.
`After the switch from exenatide to liraglu-
`tide, 3.2% of patients experienced nausea
`during the extension period, compared
`with 1.5% of individuals who continued
`liraglutide treatment.
`
`Once-weekly exenatide LAR versus
`twice-daily exenatide
`The safety and efficacy of once-weekly
`exenatide LAR (2 mg) versus twice-daily
`exenatide (10 mg) was evaluated in a
`phase 2/3 randomized open-label trial
`over 30 weeks involving 295 patients na-
`ive to drug therapy or on one or more oral
`antidiabetic drugs (24). Results from this
`trial revealed that exenatide LAR im-
`proved glycemic control significantly
`more than twice-daily exenatide. Re-
`duction in A1C was significantly greater
`with exenatide LAR versus twice-daily ex-
`enatide (21.9 vs. 21.5%, respectively;
`
`P = 0.0023), and a significantly greater
`proportion of subjects reached the A1C
`target of #7.0% with exenatide LAR ver-
`sus twice-daily exenatide (77 vs. 61%, re-
`spectively; P = 0.0039) (Supplementary
`Fig. 3). In addition, a significantly greater
`reduction in fasting plasma glucose was
`observed with exenatide LAR versus twice-
`daily exenatide (22.3 vs. 21.4 mmol/L for
`exenatide LAR and twice-daily exenatide,
`respectively; P , 0.0001).
`A progressive reduction in body
`weight was observed throughout the
`study, with both treatment groups expe-
`riencing similar reductions in weight
`from baseline (23.7 kg with exenatide
`LAR vs. 23.6 kg with twice-daily exena-
`tide; P = 0.89). The most common ad-
`verse effects seen with exenatide LAR
`versus twice-daily exenatide were nausea
`(26.4 vs. 34.5%, respectively) and in-
`jection site pruritus (17.6 vs. 1.4%, re-
`spectively). The proportion of patients
`reporting minor hypoglycemic events
`was low in both treatment arms (0 vs.
`1.1% of the study population for exenatide
`LAR and twice-daily exenatide, respec-
`tively); reports of minor hypoglycemia
`were increased in patients taking a sulfo-
`nylurea concomitantly (14.5 vs. 15.4% of
`the study population for exenatide LAR
`and twice-daily exenatide, respectively).
`The A1C and fasting plasma glucose
`reductions seen in the first 30 weeks were
`maintained throughout an extension
`study (22 weeks), where patients either
`switched from twice-daily exenatide to
`once-weekly exenatide LAR or continued
`exenatide LAR treatment (35). Individuals
`switching from twice-daily exenatide to
`exenatide LAR displayed further improve-
`ments in glycemic control, achieving the
`
`Garber
`
`same reduction in A1C from baseline
`(22.0% at week 52) as subjects who had
`been treated only by exenatide LAR. De-
`creases in body weight were similar for
`both treatment groups. As seen in the ori-
`ginal DURATION (Diabetes Therapy Uti-
`lization: Researching Changes in A1C,
`Weight and Other Factors Through Inter-
`vention with Exenatide Once Weekly) -1
`study, incidence of hypoglycemia was low
`and limited to patients who received exe-
`natide in combination with a sulfonylurea.
`
`LONG-ACTING GLP-1
`RECEPTOR AGONISTS:
`OVERVIEW OF CLINICAL
`EFFICACY—Currently, there are no
`data directly comparing the clinical effi-
`cacy of the long-acting GLP-1 receptor
`agonists (liraglutide, exenatide LAR, albi-
`glutide, taspoglutide, LY2189265). This
`section provides an indirect comparison
`of the clinical trial results achieved with
`long-acting GLP-1 receptor agonists to date.
`
`A1C
`Data from published clinical trials using
`long-acting GLP-1 receptor agonists (lira-
`glutide, exenatide LAR, albiglutide, taspo-
`glutide, LY2189265) reveal that reductions
`in A1C from baseline range from 20.87 to
`21.9% (31,33,35–39) (Fig. 1). Results
`with exenatide LAR demonstrated that
`these improvements in A1C could be
`maintained after 2 years (mean A1C de-
`crease at 2 years: 21.8%) (36). Greater
`reductions in A1C were seen with liraglu-
`tide compared with the DPP-4 inhibitor
`sitagliptin (mean A1C decrease: 21.50
`and 21.24% with 1.8 and 1.2 mg liraglu-
`tide, respectively, vs. 20.90% with sita-
`gliptin; P , 0.0001) (37).
`
`Figure 1—Change in A1C with long-acting GLP-1 receptor agonists across the clinical trials
`(24,32,36–39,41). *P , 0.01 vs. comparator; **P , 0.001; ***P , 0.0001; ###P , 0.0001 vs.
`placebo.
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`
`Overall, at least 50% of patients
`reached an A1C target of ,7.0% with
`the long-acting GLP-1 receptor agonists
`(31,33,36,37,39,40); results varied from
`52% after 16 weeks of treatment with al-
`biglutide (38) to 81% after 8 weeks of tas-
`poglutide treatment (39).
`
`Weight loss
`Body weight has been shown to signifi-
`cantly decrease in a dose-dependent man-
`ner with all of the long-acting GLP-1
`receptor agonists; results varied from
`21.4 kg after 16 weeks of treatment
`with 30 mg albiglutide (38) to 23.87 kg
`after 15 weeks of treatment with exena-
`tide LAR (2.0 mg) (40) (Fig. 2; Table 2).
`
`SBP
`In addition to their effects on glycemic
`control and body weight, the long-acting
`GLP-1 receptor agonists have been shown
`to reduce SBP in patients with type 2
`diabetes, ranging from 24.7 mmHg after
`15 weeks with exenatide LAR (33) to
`26.7 mmHg after 26 weeks with liraglu-
`tide (30) (Table 2).
`
`LONG-ACTING GLP-1
`RECEPTOR AGONISTS:
`OVERVIEW OF SAFETY AND
`TOLERABILITY
`
`Hypoglycemia
`Minor hypoglycemic events have been
`observed at a relatively low rate after the
`commencement of treatment with long-
`acting GLP-1 receptor agonists, with be-
`tween 0 and 14.5% of patients experiencing
`this side effect (24,28,38). As reported pre-
`viously, the greatest proportion of patients
`reporting minor hypoglycemic events was
`when adding treatments to a sulfonylurea
`
`background (24,27,31,32). No major hy-
`poglycemic events were reported.
`
`Gastrointestinal side effects
`Gastrointestinal effects, including nausea
`and vomiting, appear to be the most fre-
`quently reported adverse effect seen with
`the long-acting GLP-1 receptor agonists
`(Table 2). These side effects occur early on
`in the treatment, but tend to be transient
`and rarely result in patient withdrawal
`(24,32,36–39,41). After taspoglutide
`treatment, for example, nausea and vom-
`iting were usually resolved within 1 day,
`and subsequent taspoglutide administra-
`tions were less likely to induce nausea
`(39). Furthermore, a smaller proportion
`of patients reported nausea or vomiting
`after liraglutide treatment compared
`with patients treated with exenatide
`(25.5% of the study population vs. 28%
`with twice-daily exenatide; vomiting:
`6.0% of the study population vs. 9.9%
`with twice-daily exenatide) (32).
`
`Antibodies
`Antibody formation was very low in pa-
`tients treated with once-weekly GLP-1
`receptor agonists. Antibodies to albiglu-
`tide, which has 95% amino acid identity
`
`with native GLP-1, were seen in 2.5% of
`albiglutide-treated patients (38).
`Liraglutide shares 97% sequence
`identity with native GLP-1 and, across
`the LEAD trials, 8.6% of patients devel-
`oped antiliraglutide antibodies (18); how-
`ever, there were no indications from the
`clinical trial data that the formation of these
`antibodies affected efficacy (27–32,42).
`Indeed, even after 78 weeks’ treatment
`with liraglutide (26 weeks in the LEAD-6
`trial plus a 52-week extension), only 2.6%
`of patients treated with liraglutide had
`low-titer liraglutide antibodies, and these
`antibodies did not affect reductions in
`A1C in these patients (32).
`A larger proportion of patients de-
`veloped antibodies to exenatide (after 26
`weeks: 113/185 patients; 61%), and this
`is likely to be due to the lower sequence
`identity of exenatide with native GLP-1.
`Patients with high-titer exenatide anti-
`bodies exhibited a smaller decrease in
`A1C (20.5%) compared with patients
`with low-titer antibodies (21.0%). Fol-
`lowing a switch to liraglutide after 26
`weeks, patients previously treated with
`exenatide still exhibited anti-exenatide
`antibodies after treatment weeks 40
`(49.7%) and 78 (17.5%). However, the per-
`sistence of anti-exenatide antibodies did
`not affect subsequent liraglutide treatment.
`
`SUMMARY—The results achieved
`with long-acting GLP-1 receptor agonists
`appear to be superior to those achieved
`with short-acting GLP-1 receptor agonists,
`with greater improvements in glycemic
`control after once-daily liraglutide treat-
`ment compared with twice-daily exena-
`tide. Furthermore, exenatide LAR provided
`better glycemic control than exenatide
`with comparable weight loss. Trials are
`ongoing to evaluate the efficacy of ex-
`enatide LAR when compared with in-
`sulin glargine in patients with type 2
`diabetes on a metformin background with
`or without prior sulfonylurea treatment
`(DURATION-3; NCT00641056) or used
`
`Long-acting GLP-1s: efficacy and tolerability
`
`Table 2—Summary of efficacy and tolerability with long-acting GLP-1 receptor agonists
`
`Exenatide
`Taspoglutide Albiglutide LY2189265
`Liraglutide
`LAR
`21.2
`20.9
`21.5
`21.1 to 21.6 21.9
`Change in A1C (%)
`22.8
`21.4
`22.5
`Change in body weight (kg) 20.2 to 23.2 23.7
`Not reported 25.8
`25.1
`22.3 to 26.7 24.7
`Change in SBP (mmHg)
`52
`25.8
`13
`Nausea (%)
`7–29
`26.4
`22
`12.9
`Not reported
`Vomiting (%)
`4.4–17
`10.8
`Data are from the following references: 24, 27–32, 36–39, 41, and 43.
`
`Figure 2—Change in body weight with long-acting GLP-1 receptor agonists across the clinical
`trials (24,32,36–39,41). **P , 0.001; ***P , 0.0001.
`
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`
`
`as monotherapy in drug-naive patients
`(DURATION-4; NCT00676338).
`As a drug class, long-acting GLP-1
`receptor agonists increase glycemic con-
`trol in patients with type 2 diabetes with a
`low risk of hypoglycemia because of their
`glucose-dependent mechanism of action.
`This drug class has also been demon-
`strated to promote weight loss and reduce
`SBP, which could be of benefit to patients
`with type 2 diabetes, reducing their car-
`diovascular risk. Furthermore, although
`nausea is a common side effect with long-
`acting GLP-1 receptor agonists, it tends
`to be transient and, overall, long-acting
`GLP-1 receptor agonists are generally well
`tolerated. Thus, long-acting GLP-1 recep-
`tor agonists may provide an effective ther-
`apeutic option for individuals with type 2
`diabetes and are well placed to meet the
`standard of care guidelines set by the ADA
`in treating more than just blood glucose.
`
`Acknowledgments—Writing assistance was
`provided by Watermeadow Medical, funded
`by Novo Nordisk A/S. A.J.G. received re-
`search support
`from Novo Nordisk and
`GlaxoSmithKline; received advisory board/
`consultant/speaker honoraria
`from Novo
`Nordisk, GlaxoSmithKline, and Roche; served
`on the speakers’ bureaus of Merck, Novo
`Nordisk, and GlaxoSmithKline; served on
`advisory boards for GlaxoSmithKline, Roche,
`Novo Nordisk, and Merck; served as a con-
`sultant for GlaxoSmithKline, Roche, Novo
`Nordisk, and Sankyo; and attended speakers'
`bureaus for GlaxoSmithKline, Novo Nordisk,
`Merck, and Sankyo. No other potential conflicts
`of interest relevant to this article were reported.
`
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