Current Issues in GLP-1 Receptor Agonist Therapy for Type 2 Diabetes

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Abbreviations: A1C = glycated hemoglobin; ABCD = Association of British Clinical Diabetologists; ALT = alanine aminotransferase; AST = aspartate aminotransferase; BID = twice daily; BMI = body mass index; BNP = brain natriuretic peptide; CIs = confidence intervals; CrCl = creatinine clearance; DAWN Trial = Diabetes Attitudes, Wishes and Needs Trial; DPP-4 = dipeptidyl peptidase-4; DTSQ-s: Diabetes Treatment Satisfaction Questionnaire-status; EASD = European Association for the Study of Diabetes; ER = extended release; ESRD = end-stage renal disease; EXN = exenatide; FAERS = FDA Adverse Event Reporting System; FDA = United States Food and Drug Administration; FPG = fasting plasma glucose; GI = gastrointestinal; GIP = glucose-dependent insulinotropic polypeptide; GLAR = insulin glargine; GLP-1 = glucagon-like peptide-1; GLP-1 RA = glucagon-like peptide-1 receptor agonist; HOMA-B: homeostatic model assessment–β-cell function; HRQL = health-related quality of life; hs-CRP = high-sensitivity C-reactive protein; IDET = insulin detemir; IMT = intima-media thickness; IWQOL-Lite: Impact of Weight on Quality of Life-Lite; LEAD Trials = Liraglutide Effect and Action in Diabetes Trials; LIRA = liraglutide; MEN 2 = multiple endocrine neoplasia syndrome type 2; MET = metformin; MTC = medullary thyroid carcinoma; NAFLD = nonalcoholic fatty liver disease; NASH = nonalcoholic steatohepatitis; NICE = National Institute for Clinical Excellence; NIH = National Institutes of Health; OAD = oral antidiabetic agent; PAI-1 = plasminogen activator inhibitor-1; PBO = placebo; PPG = postprandial glucose; PROs = patient-reported outcomes; RA = receptor agonist; RCT = randomized controlled trial; RI = renal impairment; RORs = reporting odds ratios; SCALE = Satiety and Clinical Adiposity – Liraglutide Evidence in Non-Diabetic and Diabetic Subjects; STEMI = ST segment elevation myocardial infarction; SU = sulfonylurea; T1DM = type 1 diabetes mellitus; T2DM = type 2 diabetes mellitus; TZD = thiazolidinedione

ABSTRACTThe clinical management of

hyperglycemia in patients with type 2 diabetes mellitus (T2DM) is guided not only by published treatment algorithms, but also by consideration of recent evidence and through consultation with colleagues and experts. Recent studies have dramatically increased the amount of information regarding the use of glucagon-like peptide-1 receptor agonists (GLP-1 RAs). Topics that may be of particular interest to clinicians who treat T2DM patients include relative glycemic control efficacy of GLP-1 RAs, use of GLP-1 RAs across T2DM progression and in combination with insulin, recent data regarding GLP-1 RA safety, nonglycemic actions of GLP-1 RAs, including weight effects, and impact of GLP-1 RAs on patient quality of life and treatment satisfaction. The following review includes expert consideration of these topics with emphasis on recent, relevant reports to illustrate current perspectives.

INTRODUCTION

The gut-derived incretin hormones—glucagon-like peptide-1 (GLP-1) and glucose-dependent insulinotropic polypeptide (GIP)—have multiple physiological actions (Table 1), several of which are directly relevant to the management of type 2 diabetes (T2DM). For example, under hyperglycemic conditions,

both GLP-1 and GIP increase insulin secretion and biosynthesis, resulting in lower blood glucose levels, and GLP-1 suppresses glucagon secretion, thereby reducing inappropriate hepatic glucose production (1). GLP-1 also slows gastric emptying and decreases food intake, which are effects that may promote weight loss (1,2)

A landmark study by Nauck et al investigated the effects of GLP-1 and GIP infusion on insulin and glucagon secretion in patients with T2DM (3). GLP-1–stimulated increases in insulin secretion were similar in individuals with and without T2DM, but the insulinotropic effect of GIP was significantly reduced in the T2DM group. Additionally, GLP-1, but not GIP, suppressed glucagon secretion in participants with and without T2DM (3). Notably, GLP-1 suppression of glucagon secretion was more pronounced in participants with T2DM than in those without (3). These results suggested that GLP-1 might provide a more effective approach than GIP for improving glycemic control in patients with T2DM. Further studies verified the feasibility of administering exogenous GLP-1 to improve blood glucose levels in patients with T2DM. Nauck et al and Rachman et al confirmed that intravenous infusion of GLP-1 reduced and normalized blood glucose levels in patients with T2DM, and Nauck et al demonstrated the effectiveness of subcutaneous GLP-1 administration in lowering blood glucose in patients with T2DM (4-6). However, due to the short half-life of GLP-1, administration by continuous infusion was required to achieve optimal glycemic control, leading to the conclusion that longer-acting agents would be desirable for therapeutic purposes (5,6).

Currently, 2 classes of antihyperglycemic medications leverage protracted GLP-1 activity to improve glycemic control in patients with T2DM. One class increases endogenous GLP-1 levels by inhibiting dipeptidyl peptidase-4 (DPP-4), a ubiquitous protease that rapidly degrades GLP-1 following its secretion (1).

Table 1

Observed and Potential Clinical Effects of GLP-1 and GIP

Organ Observed and Potential Clinical Effects (1,2) GLP-1 GIP

Pancreas Observed

! Insulin secretion and synthesis X X " Glucagon secretion X

Potentiala ! Proliferation and " apoptosis of # cells X X

Brain Observed " Food intake X

Potentiala,b ! Neuroprotection X ! Progenitor cell proliferation X

Stomach Observed " Gastric emptying X

Heart Potentiala,b ! Cardiac function X ! Cardioprotection X

Bone Potentiala,b ! Formation and " resorption X Adipose tissue Potentiala ! Lipogenesis X Abbreviations: GIP, glucose-dependent insulinotropic polypeptide; GLP-1, glucagon-like peptide-1. a Possible clinical effects, based on observations from nonclinical settings. b Clinical trials in progress to assess impact of incretin-based therapies (7).

CURRENT ISSUES IN GLP-1 RECEPTOR AGONIST THERAPY FOR TYPE 2 DIABETES

Zachary T. Bloomgarden, MD, FACE1; Lawrence Blonde, MD, FACP, FACE2; Alan J. Garber, MD, PhD, FACE3; Carol H. Wysham, MD4

From the 1Department of Medicine, Division of Endocrinology, Diabetes and Bone Disease , Mount Sinai School of Medicine, New York, New York, 2Department of Endocrinology, Diabetes and Metabolism, Ochsner Medical Center, New Orleans, Louisiana, 3Departments of Medicine, Biochemistry and Molecular Biology and Molecular and Cellular Biology, Baylor College of Medicine, Houston, Texas, and 4Rockwood Diabetes and Endocrinology Center, University of Washington School of Medicine, Spokane, Washington.

Address correspondence to Zachary T. Bloomgarden, MD, FACE, Mount Sinai, 35 E 85th St, New York, NY 10028-0954. Email: [email protected]. DOI:10.4158/EP12300.RA

To purchase reprints of this article, please visit www.aace.com/reprints. Copyright © 2012 AACE.

Emphasis on Recent Evidence

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Three DPP-4 inhibitors are currently available in the United States—sitagliptin, saxagliptin, and linagliptin (8-11). In addition, vildagliptin is widely available outside the United States, alogliptin is available in Japan, and gemigliptin has been approved for marketing in Korea (12-15). The second class, GLP-1 receptor agonists (RAs), is composed of peptides that are resistant to DPP-4 degradation. Three agents are currently marketed—exenatide twice daily (BID), liraglutide, and exenatide extended release (ER) (16-18). Because they are peptides, the GLP-1 RAs are administered subcutaneously (16-18).

Although both classes of incretin-based therapies mediate their therapeutic effects by augmenting GLP-1 activity, they have distinct clinical profiles that have been attributed to the supraphysiological level of GLP-1 activity attained with GLP-1 RAs (≈8-fold increase from baseline) compared with the high physiological levels achieved with DPP-4 inhibitors (≈2-fold increase from baseline) (19,20). A summary of the relative clinical effects of GLP-1 RAs and

DPP-4 inhibitors is presented in Table 2. The therapeutic differences between GLP-

1 RAs and DPP-4 inhibitors in patients with T2DM have been demonstrated in head-to-head trials. For example, in patients inadequately controlled on metformin monotherapy (N = 61; baseline glycated hemoglobin [A1C] = 8.5%), 2-week treatment with exenatide BID resulted in significantly greater improvements in postprandial, but not fasting, glucose levels compared to sitagliptin (20). Two-hour postprandial plasma glucose levels were 133 mg/dL with exenatide BID compared to 208 mg/dL with sitagliptin (P<.0001), but both agents yielded similar reductions in fasting plasma glucose levels (−15 vs. −19 mg/dL, respectively) (20). Exenatide BID also produced significantly greater reductions in postprandial glucagon levels and caloric intake and a significant slowing of gastric emptying compared with sitagliptin (20). Furthermore, weight loss was significantly greater with exenatide BID compared to sitagliptin (−0.8 vs. −0.3 kg, respectively; P = .0056), although

more participants experienced nausea and vomiting with exenatide BID (34% and 24%, respectively) compared with sitagliptin (12% and 3%, respectively) (20). The same pattern of results was reported in a study comparing treatment with exenatide BID or sitagliptin over 4 weeks (23).

Head-to-head studies of liraglutide or exenatide ER compared to sitagliptin, added to metformin monotherapy, similarly revealed greater glycemic control (i.e., A1C reduction) and weight loss with the longer-acting GLP-1 RAs compared to the DPP-4 inhibitor (Fig. 1) (21,24,25). However, unlike the trials with exenatide BID, the longer-acting GLP-1 RAs also resulted in significantly greater reductions in fasting glucose levels compared with sitagliptin (21,24,25). Rates of gastrointestinal adverse events remained higher with the longer-acting GLP-1 RAs compared to sitagliptin. In one trial, nausea was experienced by 27%, 21%, and 5% of participants on liraglutide 1.8 mg, liraglutide 1.2 mg, and sitagliptin, respectively (21). A group treated with pioglitazone was also included in the trial comparing exenatide ER and sitagliptin (25). Nausea was reported by 24%, 10%, and 5% of participants receiving exenatide ER, sitagliptin, and pioglitazone, respectively (25).

Exenatide ER and sitagliptin monotherapy have also been compared in a large head-to-head trial (N = 820) (22). Similar to the studies combined with metformin, exenatide ER resulted in significantly greater reductions in A1C and weight (−1.53% and −2.0 kg, respectively) compared to sitagliptin (−1.15% and −0.8 kg, respectively; P<.001 for both differences) over 26 weeks, and the decrease in fasting plasma glucose was also significantly greater with exenatide ER monotherapy (22). The monotherapy head-to-head trial also included metformin and pioglitazone groups, providing a further basis of comparison for gastrointestinal adverse effects. Nausea was experienced by 11.3%, 6.9%, 4.3%, and 3.7% of participants in the exenatide ER, metformin, pioglitazone, and sitagliptin groups, respectively (22).

In addition to the class-related differences compared to DPP-4 inhibitors, the molecular characteristics of GLP-1 RAs vary, resulting in unique clinical profiles for the individual agents. One prominent effect was the difference in dosing frequency. Exenatide is synthetic exendin-4, a peptide identified in the lizard Heloderma suspectum that has 53% homology with human GLP-1 but greater potency and longer duration of action than GLP-1 (half-life of approximately 2.4 hours vs. 2 minutes, respectively) at the GLP-1 receptor (16,26). As a consequence of the longer half-life, exenatide is effective when dosed twice daily (26). Exenatide ER is exenatide delivered through hydrolysable polymer microspheres to extend the half-life to approximately 2 weeks, thereby facilitating once-weekly dosing (18,26,27). By comparison, liraglutide is a synthetic analogue of human GLP-1, with

Table 2

Clinical Effects of Incretin-Based Therapies

GLP-1 RAs Clinical Effects DPP-4 Inhibitors ++ Increased GLP-1 activity (20) + ++ Increased insulin synthesis and secretion (20) + ++ Increased !-cell function (20-22) + ++ Decreased glucagon production (20) + ++ Decreased A1C (21,22) + ++a Decreased FPG (20-22) + ++ Decreased PPG (20) +

+++b Gastrointestinal adverse effects (20-22) + Decreased gastric emptying (20) + Decreased caloric intake (20) + Weight loss (20-22)

Abbreviations: A1C, glycated hemoglobin; BID, twice daily; DPP-4, dipeptidyl peptidase-4; ER, extended release; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; PPG, postprandial glucose; RA, receptor agonist.

a For liraglutide or exenatide ER, the effect was significantly greater compared to sitagliptin; a similar effect was observed for exenatide BID and sitagliptin.

b Nausea and vomiting, generally transient and mild to moderate in intensity with GLP-1 RAs.

Fig. 1. Glycemic Control and Weight Change: Sitagliptin Compared to Liraglutide or Exenatide ER Added to Metformin (21,24,25).A1C = glycated hemoglobin; BL = baseline; ER = extended release; EXN = exenatide; LIRA = liraglutide; SITA = sitagliptina Results sustained over 52 weeks (24); b P<.05 vs. SITA; c P<.0013 vs. LIRA 1.2 mg.

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97% amino acid sequence homology to the parent sequence (17,26). The addition of an acyl chain promotes aggregation and resistance to degradation, resulting in a half-life of approximately 13 hours, which is suitable for once-daily dosing (17,26). Further differences in recommendations for the clinical use of GLP-1 RAs are reflected in the prescribing information for each agent, as summarized in Table 3 (16-18). Although the GLP-1 RAs have different clinical characteristics, all 3 are homologous to GLP-1 and therefore are not substitutes for insulin and should not be used in place of insulin to treat patients with type 1 diabetes mellitus (T1DM) or diabetic ketoacidosis (16-18).

Recent treatment guidelines for T2DM emphasize the importance of individualized care plans that consider a number of characteristics when identifying goals and selecting agents, including “…unique medical history, behaviors and risk factors, ethnocultural background, and environment” (28-31). To determine the best possible therapeutic fit in the context of a patient’s individual characteristics, clinicians need to be aware of agents’ clinical characteristics (i.e., dosing requirements, efficacy, safety considerations, potential adverse effects, and potential extratherapeutic benefits). Prescribing information is an authoritative source regarding the specific characteristics of therapeutic agents and therefore is invaluable in identifying appropriate agents for incorporation into individualized patient treatment regimens. However, consistent with evidence-based practice, therapeutic use should also be informed by the results of ongoing clinical trials and by

clinical experience. Drawing on recent evidence from these sources, the following sections will answer questions regarding:

• GLP-1 RA glycemic control efficacy• GLP-1 RA safety• Weight loss with GLP-1 RAs• Potential impact of GLP-1 RAs on

cardiovascular disease• Patient-reported outcomes (e.g., treatment

satisfaction, quality of life improvements)

What does recent evidence reveal regarding GLP-1 RA glycemic control efficacy?Comparative efficacy of GLP-1 RAs in head-to-head trials

Because the clinical characteristics of individual GLP-1 RAs vary, comparative studies of the individual agents may assist clinicians in selecting a class member that is most appropriate for an individualized patient regimen. Head-to-head trials are considered to be the most appropriate means for direct comparison of agents, and a number of these trials have been completed for the GLP-1 RAs that are currently on the market (32-36).

In trials comparing liraglutide and exenatide ER with exenatide BID, the longer-acting agents produced significantly greater changes in A1C (Fig. 2), and a similar pattern was observed for fasting plasma glucose levels (Fig. 3) (32-34). However, exenatide BID had significantly greater effects on postprandial plasma glucose levels. When compared with liraglutide, patients treated with exenatide BID had significantly greater reductions in postprandial plasma glucose following breakfast (estimated difference = 24 mg/

dL) and dinner (estimated difference = 18 mg/dL) as assessed by self-monitored blood glucose (P≤.0005) (32). Similarly, at the end of a 30-week trial comparing exenatide BID and exenatide ER, results of meal-tolerance tests demonstrated significant reductions from baseline in 2-hour postprandial glucose for both exenatide BID and exenatide ER (−124 mg/dL and −95 mg/dL, respectively), although the reduction with exenatide BID was significantly greater compared to exenatide ER (P = .0124) (33).

Improvements in glycemic control were also observed in 2 extension studies when participants were switched from exenatide BID to longer-acting GLP-1 RAs (37,38). Patients switched from exenatide BID to liraglutide experienced an additional significant A1C reduction of 0.3% (P<.0001) from the end of the initial 26-week trial period to the end of the extension period at week 40 (37). Similarly, an additional A1C reduction of 0.2% was observed from weeks 30 to 52 in patients switched from exenatide BID to exenatide ER (38).

Exenatide ER and liraglutide have also been compared in a head-to-head study. Results of this study were presented at the European Association for the Study of Diabetes (EASD) 47th Annual Meeting in 2011 and are posted at the National Institutes of Health (NIH) clinicaltrials.gov website (35,36). In terms of glycemic-control end points, liraglutide resulted in significantly greater improvement in A1C (Fig. 2) and fasting plasma glucose levels than exenatide ER (Fig. 3) (35,36). A significantly greater proportion of patients also achieved

Table 3 Summary of Label Recommendations for GLP-1 RAs

Exenatide BID (16)

Liraglutide (17)

Exenatide ER (18)

Indications and usage

Dosing (all subcutaneous)

2 " daily, before meals

1 " daily, at any time

1 " weekly

Adjunct to diet and exercise

X X X

Not first-line therapy X X Approved with basal insulin (not prandial)

X X

Warnings, precautions, contraindications

Possible thyroid tumor risk; do not use if history of MTC or MEN 2

X X

History of pancreatitis Consider

other agents Use with caution

Consider other agents

Renal impairment

Should not be used in

severe RI or ESRD

Use with caution

Not recommended in severe RI

or ESRD

Increased risk of hypoglycemia with secretagogues/insulin

X X X

Hypersensitivity X X X Severe GI disease X X

Abbreviations: BID, twice daily; ER, extended release; ESRD, end-stage renal disease; GI, gastrointestinal; GLP-1, glucagon-like peptide-1; MEN 2, multiple endocrine neoplasia syndrome type 2; MTC, medullary thyroid carcinoma; RA, receptor agonist; RI, renal impairment.

Fig. 2. A1C Effect of GLP-1 RAs in Head-to-Head Clinical Trials (32-36).A1C = glycated hemoglobin; BID = twice daily; DURATION = Diabetes Therapy Utilization: Researching Changes in A1C, Weight, and Other Factors Through Intervention with Exenatide Once Weekly; ER = extended release; EXN = exenatide; GLP = glucagon-like peptide-1; LEAD = Liraglutide Effect and Action in Diabetes; LIR = liraglutide; RA = receptor agonista P<.05 vs. comparator.


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A1C <7% with liraglutide (60.2%) compared to exenatide ER (52.7%; P = .011) (35).

Efficacy of GLP-1 RAs across T2DM disease progressionUse with oral antihyperglycemic agents

Numerous clinical trials have illustrated the efficacy of GLP-1 RAs as monotherapy and in combination with increasingly complex oral antihyperglycemic therapy regimens (21,22,25,32-34,36,39-54). In extensions of several of the clinical trials, glycemic control efficacy with GLP-1 RAs was sustained for ≥2 years (55-57). Furthermore, GLP-1 RAs have demonstrated favorable effects on glycemic control and weight in head-to-head trials compared to insulin (Fig. 4) (51,53,54,58,59).

Although GLP-1 RAs have demonstrated improved glycemic control in combination with the most commonly used oral antihyperglycemic agents, the addition of a DPP-4 inhibitor to a regimen including a GLP-1 RA would not be expected to significantly improve glycemic control because the level of GLP-1 activity is approximately 4-fold greater with GLP-1 RAs compared with DPP-4 inhibitors (GLP-1 RAs are not approved for use in combination with DPP-4 inhibitors by the U.S. Food and Drug Administration [FDA]) (20). However, contrary to this expectation, a recent study demonstrated that among patients treated with metformin and sitagliptin (N = 255), those who added exenatide BID to their regimen (ADD group) experienced significantly greater improvement in A1C compared to

those who were switched to a regimen with metformin and exenatide BID alone (SWITCH group) over 20 weeks (−0.68% vs. −0.38%, respectively; P = .012) (60). The A1C change from baseline was statistically significant for both groups (P<.001). Reduction in fasting blood glucose was significantly greater for the ADD compared to the SWITCH group, but there were no significant differences in self-monitored blood glucose profiles. Both the ADD and SWITCH groups also experienced significant weight change from baseline (−2.20 kg and −2.58 kg, respectively; P<.001 vs. baseline for both groups), although the between-group treatment difference was not statistically significant (P = .266). There was no statistically significant difference in the proportion of patients reporting treatment-emergent adverse events. Ten patients in the SWITCH group and 5 in the ADD group discontinued because of adverse events (60).

It is not clear why the combination of exenatide BID with sitagliptin improved glycemic control compared with exenatide BID alone. The study investigators speculated that the sustained action of sitagliptin, which has a half-life of 8 to 14 hours compared with the 2.4-hour half-life of exenatide, might contribute to the greater improvement (60). If this is the case, then combination of a DPP-4 inhibitor with a longer-acting GLP-1 RA may not provide the same additional benefit for glycemic control. The investigators also posited that sitagliptin may counter a decrease in endogenous postprandial GLP-1, which has been observed with exenatide BID (60).

Alternatively, sitagliptin may contribute to improved glycemic control by preventing degradation of the other major incretin hormone, GIP, through DPP-4 inhibition. However, data regarding the plausibility of this suggestion are not consistent, with some reports indicating that GIP activity is not maintained and does not augment GLP-1 action in patients with T2DM, while other studies have demonstrated restored GIP action with improved glycemic control (3,61,62). Although consideration of the mechanism behind improved glycemic control may be interesting and instructive, clinicians should bear in mind that this is the only trial to date of a GLP-1 RA combined with a DPP-4 inhibitor, that this does not represent an approved use of either agent, and that the resulting benefit should be assessed in the context of the limited safety information regarding their combined use and costs.

Recent analyses of GLP-1 RA efficacy with T2DM progression

While clinical trial results suggest that GLP-1 RAs are effective for glycemic control across T2DM disease progression, additional analyses of pooled clinical trial data have been performed to confirm this observation and to better characterize GLP-1 RA glycemic control at different stages of T2DM (63-67). Findings from these analyses are summarized in Table 4. Post-hoc analyses of pooled data from 16 exenatide BID studies and 7 exenatide ER studies were performed to assess efficacy with exenatide BID and exenatide ER according to T2DM duration (63,64). Significant A1C reduction from baseline was observed for patients with disease duration <10 years and ≥10 years in both treatment groups (Table 4) (63,64). Similarly, significant reductions from baseline were reported in fasting plasma glucose, body weight, and systolic blood pressure for both treatments in both disease duration groups (63,64). However, limitations of the post-hoc analyses precluded comparisons to determine whether changes were significantly different between groups with T2DM duration <10 years and ≥10 years (63,64).

Because patients with T2DM are likely to require the addition of antihyperglycemic agents with the progression of disease-related pathophysiological consequences (e.g., insulin resistance, β-cell failure) (68-71), assessment of efficacy according to background therapy not only provides information regarding glycemic control improvement when GLP-1 RAs are added to a specific agent or combination of agents, but may also provide insight regarding the impact of GLP-1 RAs on glycemic control as the pathophysiology of T2DM progresses. A pooled analysis of 17 trials (N = 2096) revealed significant A1C reductions from baseline with exenatide BID, regardless of background therapy (Table 4) (65). Similar results were reported for fasting plasma glucose. The duration of T2DM was 3.0 years in the diet and exercise group, 5.3-7.6 years

Fig. 3. Fasting Plasma Glucose Effects of GLP-1 RAs in Head-to-Head Clinical Trials (32-36).BID, twice daily; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention With Exenatide Once Weekly; ER, extended release; EXN, exenatide; FPG, fasting plasma glucose; GLP-1, glucagon-like peptide-1; LEAD, Liraglutide Effect and Action in Diabetes; LIRA, liraglutide; RA, receptor agonista P<.05 vs baseline; b P< .05 vs comparator.


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in patients on 1 background agent, and 6.6-9.0 years in patients on 2 background agents. Statistical analyses of between-group differences in A1C effect were not presented. A similar analysis was also performed across 7 exenatide ER trials (N = 1719; Table 4) (66). In this study, T2DM duration was 3 years in patients treated with diet and exercise, 6 years in patients on 1 background agent, and 8-10 years in patients on 2-3 background agents. Exenatide ER resulted in significant reductions in A1C from baseline, regardless of background therapy, and similar results were reported for fasting plasma glucose levels (66). As in the analysis for exenatide BID, statistical comparisons between treatment groups were not made, although A1C reductions appear to be similar (66).

An analysis of liraglutide glycemic control efficacy by diabetes stage was performed on pooled data from 7 liraglutide clinical trials (N= 4625), and early versus late T2DM progression was defined by the number of antihyperglycemic agents used by the participants prior to randomization to study treatments (≤1 agent vs. ≥2 agents) (67). Liraglutide was added to prestudy medications, which were continued throughout the trials. Reductions in A1C levels were significantly greater in the early group compared to the late group with liraglutide at both 1.2 and 1.8 mg/d dose levels (Table 4). Liraglutide 1.8 mg/d was also associated with a significantly greater proportion of patients achieving A1C <7% (72% vs. 49%, respectively; P<.0001) as well as a significantly greater improvement in β-cell function, as assessed by homeostatic model assessment–β-cell function (HOMA-B), in the early group compared to the late group, respectively (67).

The liraglutide results described above are consistent with observations from other analyses (72-74). Results from >550 patients included in the Association of British Clinical Diabetologists (ABCD) nationwide liraglutide audit revealed significant A1C reductions from baseline (P<.01) when liraglutide was added to 1 oral agent (1.4%), 2 oral agents (1.8%), 3 oral agents (1.9%), or insulin (1.0%) (72). The results also confirmed a greater A1C reduction with liraglutide in a shorter T2DM duration (0-5 years) compared with a longer T2DM duration (>10 years) (72). Furthermore, although there were no statistically significant differences among the groups receiving oral antihyperglycemic agents, those patients experienced significantly greater A1C reduction compared to participants in the insulin group (P<.01). The authors concluded that insulin necessity was a better predictor of poor liraglutide treatment response than T2DM duration (72). Similarly, preliminary studies have identified that lower limits of stimulated C-peptide secretion (≈ 2.5-3.0 ng/mL) are associated with successful transition to liraglutide monotherapy following insulin therapy (73,74). Overall, patients at all stages of T2DM progression experience significant improvements in glycemic control with GLP-

Table 4

Improvement in Glycemic Control with Exenatide across T2DM Progression:

Pooled Analyses

Post Hoc Analysis

Stratification Group

Exenatide BIDa

Exenatide ERa

Liraglutide 1.8 mgb

Liraglutide 1.2 mgb

# A1C (%) stratified by T2DM duration (63,64)c

<10 years 0.9 1.4

$10 years 1.1 1.4

#A1C (%) stratified by background therapy (65,66)d

Diet and exercise

0.8 1.5

MET 0.8 1.4 SU 1.1 TZD 0.8 MET±TZD 1.1 1.4 MET+SU 1.0 1.4 SU+other 1.6

#A1C (%) stratified by T2DM progression (67)e

“Early” %1 OAD (5.7-7.0 y)

1.55 1.38

“Late” $2 OADs (8.8-9.3 y)

1.18 0.82

Abbreviations: A1C, glycated hemoglobin; BID, twice daily; ER, extended release; MET, metformin; OAD, oral antidiabetic agent; SU, sulfonylurea; T2DM, type 2 diabetes mellitus; TZD, thiazolidinedione.

a Significant A1C improvement from baseline observed regardless of T2DM duration or background therapy (P<.0001, all groups).

b Significant difference for all within-treatment “early” vs. “late” comparisons (P<.005). c Baseline A1C 8.2-8.6%. d Baseline A1C 7.8-8.8%. e Baseline A1C 8.5-8.6%, except 7.8% for “late” 1.2 mg LIRA group.

Table 5

Study Outcomes: Exenatide BID and Liraglutide Combined with Basal Insulin

Study EXN BID or PBO Added to GLAR

(30-week blinded RCT) (75)a

IDET or Nothing Added to LIRA 1.8 mg

(26-week open-label RCT) (76)b

Treatment regimen EXN BID (n = 137)

PBO (n = 122)

P Value

IDET (n = 162)

Nothing (n = 161)

P Value

Baseline A1C (%) 8.3 8.5 7.6 7.6 T2DM duration (y) 12 12 8.6 8.5 # A1C (%) 1.74 1.04 <.001 0.51 0.02 <.0001 # weight (kg) 1.8 1.0 <.001 0.16 0.95 .03 Hypoglycemia (events/patient/year)

1.4 1.2 0.49 0.286c 0.029c .004

Withdrawals due to adverse events (n)

13 1 4 6

Abbreviations: A1C, glycated hemoglobin; BID, twice daily; EXN, exenatide; GLAR, insulin glargine; IDET, insulin detemir; LIRA, liraglutide; MET, metformin; PBO, placebo; RCT, randomized controlled trial; SU, sulfonylurea. a Concomitant antihyperglycemic therapies were continued. b In approximately one-third of participants, SU was discontinued at run-in, but the MET dose remained unchanged. c Excluding outlier in control group with 25 episodes of minor hypoglycemia.


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1 RAs. However, data from liraglutide trials suggest that greater glycemic control benefits may be realized earlier in T2DM progression.

Efficacy of GLP-1 RAs combined with insulinTitration of basal insulin based on fasting

blood glucose levels has been recommended as a means to reach glycemic goals in patients with T2DM who have not done so with oral antihyperglycemia agents (30,31). However, as many as 50% of patients still do not achieve target blood glucose levels using this approach (75). Both exenatide BID and liraglutide have been approved for use in combination with basal insulin in patients with T2DM (16,17). The trials performed to support this indication were designed to investigate different aspects of the use of GLP-1 RAs in combination with basal insulin. The addition of exenatide BID to regimens including insulin glargine was investigated because it was postulated that the effects of exenatide BID on prandial glucose control would complement those of insulin glargine on fasting blood glucose levels (75). In the study by DeVries et al, insulin detemir was added to regimens including once-daily liraglutide to assess the efficacy of the novel intensification sequence of GLP-1 RAs prior to insulin. Characteristics and key results of the main, randomized portions of these trials are presented in Table 5 (75,76).

The use of GLP-1 RAs in combination with basal insulin has been associated with improved overall glycemic control, as indicated by significant decreases in A1C levels compared to either basal insulin or GLP-1 RA alone (Table 5) (75,76). Consistent with the hypothesis of Buse et al that exenatide BID would improve glycemic control in combination with insulin glargine by decreasing postprandial glucose levels, the combination of these agents did not significantly decrease fasting plasma glucose levels but did significantly reduce all nonfasting self-monitored blood glucose levels (75). Additionally, the increase in total daily insulin dose was significantly lower in the group receiving exenatide BID and insulin glargine (13 U/d) compared with the group receiving insulin glargine alone (20 U/d; P = .03) (75). By comparison, the addition of insulin detemir to liraglutide 1.8 mg significantly decreased both fasting and postprandial glucose levels (76). Results similar to those at 26 weeks with liraglutide 1.8 mg and insulin detemir have been reported following an additional 26-week extension (77).

It is also worth noting that participants experienced significant weight loss when exenatide BID was added to insulin glargine, and participants did not gain weight when insulin detemir was added to a regimen that included liraglutide (75,76). With regard to adverse events, only 1 participant, in the placebo group, experienced major hypoglycemia in the trial assessing exenatide BID with insulin glargine, and minor hypoglycemia rates were similar (75). No

participants experienced major hypoglycemia in the trial assessing insulin detemir with liraglutide, and minor hypoglycemia rates were 0.029 and 0.286 events per participant year for liraglutide with or without insulin detemir, respectively (P = .004) (76). Gastrointestinal adverse events (i.e., nausea, vomiting, constipation, or diarrhea) were experienced by a greater proportion of participants treated with exenatide BID and insulin glargine than by those treated with insulin glargine alone (75). Serious adverse events were reported by 3.8% and 5.5% of participants receiving liraglutide with or without insulin detemir, respectively, with no clear pattern and most being considered unrelated to treatment (76).

Overall, the data described above indicate that a GLP-1 RA added to insulin or insulin added to a GLP-1 RA improves glycemic control, even in patients with long-standing T2DM. Additional evidence suggests that other patient populations may also benefit from the addition of GLP-1 RAs to insulin regimens. Obese patients with severe insulin resistance may require extremely high insulin doses (>100 U/d) to overcome insulin resistance (78). Treatment with high insulin doses may lead to a continuing cycle of weight gain, increasing insulin resistance, and growing insulin requirements (78). In an observational case series of 15 obese patients with T2DM and high insulin requirements, treatment with U-500 insulin and liraglutide for 12 weeks resulted in significant reductions from baseline in A1C (1.4%; P = .0001), weight (11.2 lb [5.1 kg]; P = .0001), and total daily insulin dose (28%; P = .0001) (GLP-1 RAs are currently not approved for use in combination with U-500 insulin by the U.S. FDA) (78).

There is also increasing evidence, although predominantly from small studies, that GLP-1 RAs may be beneficial as adjunct therapies to insulin in T1DM (GLP-1 RAs are currently not approved for use in patients with T1DM by the U.S. FDA). Previous studies with exenatide have reported:

• Slowed gastric emptying, normalized postprandial glucagon levels, and normalized postprandial glucose following individual doses in 9 adult participants with T1DM and no residual β-cell activity (endogenous C-peptide response <.01 nmol/L) (79)

• Slowed gastric emptying and reduced postprandial glucose excursions, but not suppressed glucagon levels, in 8 pediatric patients on insulin pump therapy or multiple daily insulin injections and with little or no residual β-cell activity (80)

Most recently, at the American Diabetes Association’s 72nd Scientific Sessions in 2012, results of 6-month treatment with high-dose exenatide (10 mcg, 4 times daily) in 14 adult patients with long-standing T1DM were reported (81). Exenatide significantly reduced weight, postprandial blood glucose,

and daily insulin requirements but increased fasting glucose levels, such that there was no significant change in overall glycemic control. In addition, the insulin sensitivity index (mg/m2/min per mU/mL) was significantly increased with exenatide treatment (81).

Similarly, previous trials with liraglutide revealed:

• Significantly reduced insulin doses in adult T1DM patients with and without residual β-cell function and reduced time in hypoglycemia for those with residual β-cell function over 4 weeks of treatment (82)

• Decreased glycemic excursions, significantly decreased glucose concentrations, and decreased basal and bolus insulin doses at 1 week and 24 weeks in patients with T1DM and no measurable residual β-cell activity (83)

More recently, investigators reported significant reductions in the percent of time spent in hyperglycemia (>45%) and insulin dose (19-26%) as well as decreased weight in patients with T1DM who continued with liraglutide for 1 year (84). In addition, significant reductions in A1C, bolus insulin dose, and body weight were observed in 15 obese adult patients with T1DM and no residual β-cell function who were treated with liraglutide 1.8 mg over 6 months (84).

Because many patients in these studies did not have residual β-cell activity at the beginning or end of the study periods, improvements in glycemic control cannot be readily attributed to GLP-1 RA–stimulated increases in glucose-dependent insulin production (84). It is possible that the clinical effects of GLP-1 RAs in patients with T1DM are due to slowed gastric emptying and the corresponding reduction in glycemic excursions. It is also possible that glucagon suppression and effects on insulin sensitivity play roles, although these were not observed as consistently or reported as often as effects on gastric emptying.

Additional factors that may impact responsiveness to GLP-1 RAs

The previous section on recent analyses of GLP-1 RA efficacy across T2DM progression highlighted a number of studies conducted to identify clinical characteristics (e.g., T2DM duration) associated with GLP-1 RA therapeutic success. In general, such approaches have been disappointing, particularly because many additional factors (e.g., patient treatment adherence) can impact treatment efficacy (85). There are situations, however, in which underlying genetic traits (e.g., autosomal dominant traits leading to the development of maturity-onset diabetes of the young or potassium channel mutations) are used to identify treatments that have clear mechanistic advantages (85). There is also some increasing evidence regarding underlying individual characteristics that may have the


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potential to impact the efficacy of GLP-1 RAs in the treatment regimens of individual patients. Such insights could potentially guide clinicians to develop truly individualized therapeutic regimens.

For example, the ability to identify patients who are likely to develop antibodies against a given GLP-1 RA agonist might assist clinicians in determining the most appropriate GLP-1 RA for a given individual. In clinical trials, greater proportions of patients developed antibodies against exenatide BID and exenatide ER than against liraglutide (86-88). Low titers of anti-exenatide antibodies developed in 31.7% of participants in the exenatide BID group after 30 weeks of treatment and in 45.0% of participants in the exenatide ER group at 24-30 weeks (89). The proportions of participants developing high anti-exenatide antibody titers were 5.0% at 30 weeks and 11.8% at 24 to 30 weeks in the exenatide BID and exenatide ER groups, respectively (89). In a subset of participants who were tested, anti-exenatide antibodies did not react with human GLP-1 or glucagon (89). Reductions in A1C were comparable between low-titer and antibody-negative patients treated with exenatide BID (−1.0%, both groups) or exenatide ER (−1.5 % vs. −1.6%, respectively) (89). However, there was a nonsignificant trend toward reduced efficacy with increasing titer in the exenatide BID group (89). Among patients treated with exenatide ER, there was a significant trend toward reduced efficacy with higher antibody titer, with an attenuated mean A1C reduction of 0.6% in the high titer group (89). In liraglutide clinical trials, 8.3% of liraglutide-treated participants developed low titers of anti-liraglutide antibodies (89). The proportion of patients with antibodies that cross-reacted with GLP-1 was in the range of 2.1% to 4.9%, and 0% to 2.7% developed antibodies that neutralized liraglutide in vitro (87). However, the effect of liraglutide on A1C was the same in antibody-negative and antibody-positive groups (87). Interestingly, among patients switched from exenatide BID to liraglutide, those with the highest persistent anti-exenatide antibody titers (>50% bound/total radioactivity) experienced the greatest A1C reductions (range, 0.5% to 1.2%) (Fig. 5) (87).

Potential contributions of GLP-1 receptor genetic polymorphisms to GLP-1 RA clinical responses have also been investigated. Although studies have failed to identify a relationship between GLP-1 receptor polymorphisms and the development of obesity or diabetes, several studies have identified individual GLP-1 receptor polymorphisms associated with reduced responses to receptor agonists (90-95). In individuals without diabetes, Sathananthan et al identified reduced insulinotropic responses associated with 2 GLP-1 receptor polymorphisms (94). Using in vitro methodologies, Beinborn et al demonstrated reduced binding affinity, decreased agonist potency, and abolished

metabolite action associated with GLP-1 receptor polymorphism T149M (93). Further investigation of this polymorphism confirmed lack of responsiveness to the peptide ligand, but revealed preserved responsiveness to a small molecule allosteric modulator (95). Essentially, the small molecule rescued the loss of peptide function associated with the T149M polymorphism. Although these results are preliminary, they suggest the possibility of an individualized therapeutic approach that employs specific agents to manage a disease based on an individual’s genotype.

What does recent evidence reveal regarding GLP-1 RA safety?Thyroid tumor risk

In a review of the liraglutide approval process, representatives of the U.S. FDA highlighted 3 safety topics that were carefully considered —the potential risk of thyroid tumors and/or cancer, the potential risk of pancreatitis, and cardiovascular safety (96). Precautionary statements on the potential risks of pancreatitis and thyroid tumors/cancer were included in the liraglutide label on approval, and an additional statement concerning reports of acute renal failure has also been added (17,97). Similarly, precautions regarding pancreatitis and reports of acute renal failure have been added to the prescribing information for exenatide BID since its initial approval, and the prescribing information for exenatide ER includes precautionary statements regarding potential pancreatitis risk, risk of thyroid tumors/cancer, and reports of acute renal failure (16,18,97). Accordingly, this section focuses on recent evidence that has been collected in order to clarify any likelihood of potential risks for thyroid tumors/cancer, pancreatitis, and renal failure with GLP-1 RAs; a subsequent section will focus on cardiovascular safety and effects.

In mice and rats, once-daily liraglutide or continuous exenatide infusion over 9 or 12 weeks, respectively, resulted in statistically significant increases in plasma levels of calcitonin, which is a clinical biomarker for the detection of medullary thyroid carcinoma (MTC) (98). Furthermore, calcitonin levels increased progressively over 104 weeks of liraglutide treatment (98). Statistically significant increases in C-cell hyperplasia were also reported with both exenatide and liraglutide in mice and with liraglutide in rats, and liraglutide was associated with a statistically higher incidence of C-cell tumors in rats (98). However, the possible relevance of these observations to humans is currently unknown, because there are distinct species differences between rodents and humans (96,98-101). Of concern is whether there would be a potential effect of GLP-1 RAs on the development of MTC, which arises from calcitonin-producing C-cells, is aggressive, and has a poorer prognosis than the usually highly treatable, and more common, papillary and follicular thyroid cancers (102).

Although GLP-1 RA treatment clearly and significantly increased thyroid C-cell hyperplasia and tumors as well as serum calcitonin levels in rodents, such effects have not been demonstrated in humans. In more than 4 years of postmarketing experience, only 9 cases of thyroid cancer (3 papillary, 6 unspecified) were reported in 840,000 patient-years of treatment with exenatide BID (103). C-cell hyperplasia was identified in 1.3 cases per 1000 patient-years compared to 1.0 case per 1000 patient-years for liraglutide and comparator-treated patients, respectively, but there were no cases of MTC among the liraglutide-treated patients (17,104).

Calcitonin levels were also measured in liraglutide clinical trials, although not in trials for exenatide (17,18,103). Levels of calcitonin <10 ng/L are considered to indicate the absence of MTC, while levels >100 ng/L are highly predictive of MTC (96). Patients with MTC usually have serum calcitonin levels >50 ng/L (17). One liraglutide-treated patient, but no comparator-treated patients, developed calcitonin levels >50 ng/L; the same patient had an elevated pretreatment calcitonin level of 10.7 ng/L (17). However, overall, in the 6 phase 3 Liraglutide Effect and Action in Diabetes (LEAD) trials for liraglutide clinical development, calcitonin levels (105):

• Were generally low and well below the upper limit of normal over the entire trial period, including 2 trials that ran for 104 weeks

• Were generally not different compared to active comparators and just above the lower limit of quantification

• Demonstrated no consistent pattern for shifting to a higher level

• Were above 20 ng/L for 1.7% and 1.9% of participants in the liraglutide and active comparator groups, respectively, after 104 weeks (105)

Mean calcitonin levels for exenatide BID and liraglutide from the LEAD-6 trial are presented in Figure 6 (105).

A number of factors may help to explain observed differences between rodents and humans. For example, thyroid C-cell density is similar in humans and nonhuman primates, but mice and rats have C-cell densities 22-fold and 45-fold higher, respectively, than humans (98). Notably, neither calcitonin levels nor C-cell hyperplasia increased with long-term liraglutide treatment in nonhuman primates (98). C-cells in normal thyroid tissue from rats and mice also express detectable levels of GLP-1 receptors (98,100,101) Furthermore, 100% of rat MTC tissues expressed high levels of GLP-1 receptors (101). In contrast, 2 of the cited studies detected no GLP-1 receptors in normal human C cells, while the third study identified expression in a subset of samples (5/15) (98,100,101). The prevalence of GLP-1 receptor expression in human thyroid cancer samples was also lower than the 100% level identified in rats (100,101). GLP-1 receptor expression was identified in


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27% and 50% (6 of 12) of human MTC samples in 2 different studies, respectively (100,101). Although these data might provide information on GLP-1 receptor localization, they do not indicate whether these receptors responded to GLP-1 and do not indicate that these receptors played any role in C-cell tumor formation. Moreover, recent data from studies in mice have demonstrated that C-cell hyperplasia mediated by GLP-1 RAs is not associated with activation of the RET proto-oncogene, which is often involved in the development of C-cell cancer in humans (99).

In general, data do not seem to suggest that the increased rate of tumor formation with GLP-1 RAs in rodents translates to increased thyroid cancer risk for humans treated with GLP-1 RAs. One reference has reported a significantly increased risk of thyroid cancer and pancreatitis with exenatide based on analysis of the FDA Adverse Event Reporting System (FAERS) database (106). However, the FDA specifically states that, “…FAERS data cannot be used to calculate the incidence of an adverse event or medication error in the US population…” due to limitations that include uncertainty regarding a causal relationship between the product and an event, incomplete reporting, and the potential influence of external factors (e.g., publicity) on event reporting (107). The EASD published a commentary that cautions against drawing conclusions based on this study because of the database limitations noted above as well as methodological weaknesses, such as a lack of consideration of confounding factors and inadequate diagnosis definition and verification (108).

The FDA also concluded that increased thyroid carcinomas in rodents treated with liraglutide translated to a low risk for humans

(96). Both liraglutide and exenatide ER have been approved by the FDA subsequent to this determination (17,18). However, the FDA required additional studies for both agents and included label precautions (113,114). Until more information is available, the following points should be considered (17,18,111,112):

• Liraglutide and exenatide ER are not recommended as first-line therapy, although they may be considered for monotherapy in patients who are unable to use other first-line therapies because of lack of efficacy, contraindications, and/or intolerance

• Liraglutide and exenatide ER are contraindicated in patients with a personal or family history of MTC or with multiple endocrine neoplasia syndrome type 2 (MEN 2)

• The value of routine calcitonin and/or ultrasound monitoring is unknown, and such monitoring may have the potential to increase the rate of unnecessary procedures

• Patients with thyroid nodules identified on neck examination or neck imaging or with elevated serum calcitonin levels obtained for other reasons should be referred to an endocrinologist

• All cases of MTC should be reported to a healthcare professional’s state cancer registry, regardless of drug treatment (http://www.naaccr.org/ Membership/MembershipeDirectory.aspx)

Pancreatitis riskLabel statements cautioning about

the possibility of increased risk of acute pancreatitis with GLP-1 RAs were added

based on exenatide postmarketing data and liraglutide clinical trial reports, rather than the establishment of a causal relationship or any understanding of an underlying mechanism by which incretin-based therapies might contribute to increased pancreatitis risk (16-18,96). In fact, it has been difficult to discern whether GLP-1 RAs contribute to increased risk of pancreatitis, because the baseline risk for people with diabetes is already 1.5 to 3 times greater than for individuals without diabetes (113-115). To better characterize the potential impact of GLP-1 RAs on pancreatitis, the FDA has requested that the sponsors of liraglutide and exenatide meet postmarketing requirements, including database analyses and mechanistic studies (109,110).

Multiple analyses of insurance claim databases have been performed, assessing the risk of pancreatitis with exenatide or sitagliptin compared to comparator treatments (115-120). A major advantage of claims-based analyses is the large size of the study population, which provides statistical power for the detection of rare outcomes (118). For example, 3 of the cited analyses reported inclusion of >24,000 subjects treated with exenatide BID, and the other 2 included >6000 exenatide-treated patients (115-120). Additionally, subjects are generally representative of insured patients who are typically seen in clinical practice, including those with comorbidities (118). Limitations include the potential for inaccurate diagnoses, incomplete recording of risk factors, and population bias resulting from selective prescription of agents (118,119). Some of these limitations can be mitigated through approaches such as diagnosis confirmation by blinded review of individual medical records and inclusion of matched controls (118). Each of the cited claims-based analyses identified no increased risk of pancreatitis in patients treated with exenatide BID (115-120). More specifically, compared with control populations, risk estimate ratios and 95% confidence intervals (CIs) for acute pancreatitis in patients taking exenatide BID were 1.0 (0.6-1.7) (115), 0.9 (0.6-1.5) (114), 0.2 (0.0-1.4) (117), and 0.95 (0.65-1.38) (119).

In contrast to the findings of the insurance claims database analyses described above, one FAERS database analysis identified a dramatic increase (>10-fold) in pancreatitis risk with exenatide (106). Although the FAERS database represents the largest public source of drug safety data, as was previously noted, it is not an appropriate data source for determining event incidence, and the methodology of this study received significant criticism (107,108). Furthermore, these results are inconsistent with those of other epidemiological analyses (108). An additional FAERS database analysis addressed criticisms raised by the EASD commentary (108,121). The investigators of this study presented their results as reporting odds ratios (RORs) to emphasize the fact that the data represent a reporting imbalance rather than a risk ratio (121).

Fig. 4. A1C and Weight Change: GLP-1 RAs vs Insulin (51, 53, 54, 58, 59).A1C, glycated hemoglobin; BID, twice daily; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention With Exenatide Once Weekly; ER, extended release; EXN, exenatide; GLP-1, glucagon-like peptide-1; INS, insulin; LEAD, Liraglutide Effect and Action in Diabetes; LIRA, liraglutide; RA, receptor agonista EXN BID vs insulin glargine (3 trials, 26-52 weeks) or biphasic insulin aspart 70/30 (1 trial, 16 weeks); b Vs insulin glargine, 26-week outcomes; c Vs insulin detemir, 26-week outcomes; d P<.05 vs insulin.


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Additionally, Raschi et al performed a temporal analysis that revealed no significant reporting bias until after the 2008 FDA alert (121). Based on this adjusted analysis, the investigators concluded that the results were consistent with those of previous epidemiological studies, which indicated no increased risk of pancreatitis with incretin-based therapies (121).

The FDA has requested postmarketing studies to assess potential mechanisms by which GLP-1 RAs might contribute to the development of acute pancreatitis (109,110). However, the value of using animal studies to this end is unclear (122,123). Animal studies often utilize short-term treatment of healthy animals, without risk factors for pancreatitis that have been identified in humans (e.g., obesity, dyslipidemia, and gall bladder disease) (123). Animal models of pancreatitis have been developed, although their relevance to human pathophysiology is uncertain (123). Furthermore, animal studies for the assessment of mechanisms by which GLP-1 RAs might promote acute pancreatitis have yielded variable results (122-125). For example, in a recent study in rats, exendin-4 increased relative pancreatic weight and led to changes in pancreatic duct glands and epithelium, but there was no histological evidence of pancreatitis, increased lipase activity, or carcinoma (124). In a mouse model of chronic pancreatitis, a greater proportion of pancreatic tissue had indications of pancreatitis in animals treated with exendin-4 compared with untreated animals (124). By comparison, approximately 2% of mice, but not rats, developed microscopic pancreatitis over 2 years of liraglutide treatment, and neither pancreatitis nor preneoplastic lesions were identified in monkeys dosed for 87 weeks (125).

There has been no causal relationship established to date between the use of GLP-1 RAs and the development of pancreatitis. However, it is prudent to adhere to the current recommendations (16,111,112):

• Observe patients carefully for signs and symptoms of pancreatitis

• If pancreatitis is suspected, • Discontinue GLP-1 RA and other

potentially contributing medications • Perform confirmatory tests • Initiate appropriate management • Do not restart a GLP-1 RA if

pancreatitis is confirmed• In patients with a history of pancreatitis,

consider other antihyperglycemic therapies. If GLP-1 RAs are used, then significant caution should be exercised

Renal safety considerationsProduct-specific prescribing information

for GLP-1 RAs provides guidance regarding use in patients with identified renal insufficiency (Table 6) (16-18).

Evidence from clinical trials and insurance claims database analyses has not indicated direct nephrotoxicity due to GLP-1 RAs or increased risk of acute renal failure with exenatide or liraglutide (16-18,126-130).

However, cases of acute renal failure have been reported in individuals receiving GLP-1 RA therapy (16,17,131-137). Common characteristics of acute renal failure cases have included 1 or more gastrointestinal symptoms, dehydration/hypovolemia, and concomitant use of agents known to affect renal function (e.g., angiotensin-converting enzyme inhibitors, angiotensin II receptor blockers, and diuretics) (16,17,131-137). In many cases, renal impairment was totally or partially reversed with supportive treatment and discontinuation of potentially causative agents (16,17,131-137).

Because exenatide BID and exenatide ER are predominantly eliminated through glomerular filtration, circulating levels of these GLP-1 RAs may be increased in patients with renal impairment (16,18,138). Prescribing information for both agents recommends cautious use in patients with moderate renal impairment and warns against use in patients with severe renal impairment or end-stage renal disease (ESRD) (Table 6) (16,18,138). In contrast, the kidneys are not a major route of clearance for liraglutide, and no clear pharmacokinetic trend related to impaired renal function has been identified (17,128,139). Consistent with these characteristics, there are no recommendations against the use of liraglutide in patients with renal impairment, although caution is advised when initiating liraglutide or escalating doses in these patients (Table 6) (17).

A causal association between the use of GLP-1 RAs and the occurrence of acute renal failure has not been established. However, clinicians should follow the recommendations shown in Table 6 for the use of GLP-1 RAs in patients with decreased kidney function. Because caution is urged when initiating or escalating GLP-1 RA in patients with renal insufficiency, healthcare professionals should be aware of a patient’s renal status when prescribing these agents. They should also be

aware of the above case reports and should be prepared to identify and provide appropriate treatment for patients with T2DM who develop impaired renal function, whether or not they have been using GLP-1 RAs.

What does recent evidence reveal regarding the potential cardiovascular impact of GLP-1 RAs?

In preliminary assessments of the cardiovascular safety of GLP-1 RAs, analyses of clinical trial data have revealed no increased risk of cardiovascular events with exenatide BID or liraglutide (140,141). Similarly, analyses of insurance claim databases have revealed lower risk of cardiovascular events, including congestive heart failure, in patients receiving exenatide compared to other antihyperglycemic medications (142,143). Studies also have demonstrated no QT prolongation with exenatide BID, exenatide ER, or liraglutide, further reinforcing the cardiovascular safety profiles of these agents (144-147). Clinical trials have revealed small but significant heart rate increases of approximately 0.5 to 4.0 beats per minute with GLP-1 RAs (34,54,103,140). The relevance of the heart rate increases is unclear, as they occur in the context of decreased blood pressure and have not been associated with increases in cardiovascular or arrhythmia-related adverse events (34,54,140). Therefore, further verification of the safety of GLP-1 RAs is needed, and long-term clinical trials in populations at increased risk of cardiovascular events are currently in progress (7). Nevertheless, results suggesting the relatively safe cardiovascular profiles are consistent with other clinical characteristics of GLP-1 RAs, including reduced blood pressure, improved lipid levels, and low risk of hypoglycemia.

GLP-1 RA effects on blood pressureA recent meta-analysis of randomized

Table 6

GLP-1 RA Use in Patients with Renal Impairment

Renal Status Exenatide BID (16) Exenatide ER (18) Liraglutide (17) Mild impairment (CrCl 50-80 mL/min)

No adjustment or recommendation

No dose adjustment

Use with caution when initiating or escalating dosesa

Moderate impairment (CrCl 30-50 mL/min)

Use caution when initiating or

escalating dosesa Use with cautiona

Severe impairment (CrCl <30 mL/min) or ESRD

Should not be used Not recommended

Renal transplant Use with caution Abbreviations: BID, twice daily; CrCl, creatinine clearance; ER, extended release; ESRD, end-stage renal disease. a Hypovolemia due to nausea/vomiting may worsen renal function.


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controlled GLP-1 RA trials revealed modest reductions in systolic and diastolic blood pressure. Systolic blood pressure was reduced by 3.57 mm Hg (95% CI: − 5.49 to −1.66) and diastolic blood pressure was reduced by 1.38 mm Hg (95% CI: −2.02 to −0.73) (148). Blood pressure changes were also in this range in head-to-head clinical trials of GLP-1 RAs, and were similar for exenatide BID compared to liraglutide, exenatide BID compared to exenatide ER, and exenatide ER compared to liraglutide (32,33,35,36). Although blood pressure changes observed with GLP-1 RAs are not as large as those typically achieved with antihypertensive agents, a meta-analysis of results from the LEAD clinical trial program demonstrated that liraglutide administered in a background of antihypertensive medication resulted in an additional significant decrease in systolic blood pressure relative to placebo (−2.03 mm Hg), indicating that GLP-1 RAs may provide added benefit for T2DM patients trying to achieve blood pressure goals (149).

GLP-1 RAs may decrease blood pressure through multiple mechanisms. For example, better glycemic control could improve endothelial function or GLP-1 receptor activation could promote vasodilation through direct actions or effects on the sympathetic nervous system. Decreased blood pressure could also be the consequence of increased urine excretion and natriuresis, vasodilation associated with increased insulin production, or weight loss (150). The relationship between changes in blood pressure and weight is not completely clear. In the LEAD trials, decreases in blood pressure preceded weight loss, indicating that the at least the immediate effect

of liraglutide on blood pressure is independent of weight loss (150). A small, retrospective study also found a significant decrease in systolic blood pressure to be independent of weight loss in patients receiving exenatide in combination with insulin over 26 weeks (151). However, a meta-analysis of exenatide BID clinical trials identified a weak correlation between weight loss and decreased blood pressure over 6 months, and patients who lost weight were more likely to experience decreased blood pressure in a pooled analysis of exenatide ER trials (152,153). A reasonable explanation may be that GLP-1 RAs can decrease blood pressure through multiple mechanisms, including some that are associated with weight loss and some that are not (36).

GLP-1 RA effects on lipidsFigure 7 summarizes changes in several

lipid fractions (total cholesterol, low-density lipoprotein cholesterol, triglycerides, and high-density lipoprotein cholesterol) observed in head-to-head trials of GLP-1 RAs (32,33,35). In general, the agents show similar trends, with significantly greater reductions in total cholesterol and low-density lipoprotein cholesterol for exenatide ER compared to exenatide BID and in triglyceride levels for liraglutide compared to exenatide BID (32,33,35).

It is currently not clear whether lipid changes associated with GLP-1 RA therapy are a consequence of weight loss or other actions (150). However, recent data suggest a role for direct actions of GLP-1 RAs on lipid metabolism. In 15 normolipidemic and normoglycemic men, single exenatide

doses (10 mcg) significantly suppressed plasma concentrations of triglyceride-rich lipoprotein apoB-48 following infusion of a high-fat, mixed macronutrient directly into the duodenum (154). A study of liraglutide in patients with T2DM yielded similar results (155). Following 3 weeks of treatment with liraglutide 1.8 mg, participants were served a standardized fat-rich meal. Postprandial triglyceride and apoB-48 levels decreased significantly in patients receiving liraglutide compared to those receiving placebo, with no difference in free fatty acid levels or in the postprandial rate of gastric emptying between the 2 groups (155). Low-density lipoprotein and total cholesterol levels were also significantly lower with liraglutide compared to placebo (155).

The clinical impact of the relatively modest lipid changes with GLP-1 RAs is also unclear. In terms of the lipid changes required to achieve significant outcomes, a decrease of 39 mg/dL in low-density lipoprotein cholesterol has been demonstrated to reduce all-cause mortality (10%), coronary disease mortality (20%), and occurrence of major vascular events (22%) (156). For triglycerides, a decrease of ≈9 mg/dL has been associated with a decreased risk of coronary events (5%) (157). However, the strongest evidence to date from randomized controlled trials only supports therapeutic targeting of low-density lipoprotein cholesterol or non–high-density lipoprotein cholesterol, and improved outcomes or benefits thought to be associated with increasing high-density lipoprotein cholesterol or decreasing triglyceride levels have not been consistently demonstrated (158-161). Changes in non–high-density lipoprotein

Fig. 5. A1C Change With Liraglutide by Exenatide Antibody Status (87).A1C, glycated hemoglobin; Ab, antibody; EXN, exenatide; LIRA, liraglutidea >2.23% to ≤20% antibody-bound/total radioactivity; b >20% antibody-bound/total radioactivity.

Fig. 6. Calcitonin Levels With Liraglutide and Exenatide BID (LEAD-6 Trial) (105).BID, twice daily; EXN, exenatide; LEAD, Liraglutide Effect and Action in Diabetes; LIRA, liraglutide; LS, least squares


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cholesterol levels associated with GLP-1 RA treatment are consistent with recommended therapeutic goals, but the magnitude of the changes produced is relatively small, and no benefits on cardiovascular outcomes have been demonstrated to date.

Low risk of hypoglycemia with GLP-1 RAsSevere hypoglycemia has been identified

as a risk factor that contributes to an increased frequency of cardiovascular events, cardiovascular death, and all-cause mortality in large, prospective trials designed to assess the impact of intensive glycemic control on cardiovascular outcomes in patients with T2DM (Fig. 8) (162,163). In this context, the low risk of hypoglycemia associated with GLP-1 RAs is particularly important.

Figure 9 summarizes hypoglycemia outcomes compared to placebo or antihyperglycemic agents for GLP-1 RAs used as monotherapy or in combination with metformin (22,25,45,50,56,165). In general, rates of hypoglycemia were not significantly different for GLP-1 RAs compared to placebo, metformin, or pioglitazone, which are also associated with a low risk of hypoglycemia, but hypoglycemia rates were significantly lower than with glimepiride (22,25,45,50,56,165). It is important to note, however, that rates of hypoglycemia with GLP-1 RAs may be higher when they are used with insulin secretagogues or insulin (16-18). Reducing the dose of insulin secretagogues or insulin may be appropriate when initiating combination treatment with a GLP-1 RA to prevent hypoglycemia (16-18).

GLP-1 RA effects on additional cardiovascular risk factors

GLP-1 RAs have been linked to improvements in cardiovascular risk factors other than blood pressure, lipid levels, and hypoglycemia. For example, several studies have revealed an improvement in biomarkers for cardiovascular disease and inflammation in patients with T2DM following treatment with GLP-1 RAs. In a year-long study of patients who were treated with metformin, the addition of exenatide BID significantly increased adiponectin and decreased leptin and high-sensitivity C-reactive protein (hs-CRP) compared to the addition of insulin (166). In a separate study, exenatide BID significantly increased adiponectin and decreased tumor necrosis factor-alpha (TNF-α) and hs-CRP compared with glimepiride (167). The extent to which concomitant weight loss contributed to these effects is not completely clear, as the changes were found to be independent of weight loss in the former study, but changes in adiponectin and TNF-α correlated with a decrease in body mass index (BMI) in the latter study (166,167). A more recent study found that 12-week treatment with exenatide BID was associated with reduced levels in a number of inflammatory cytokines (e.g., monocyte chemoattractant protein-1, serum amyloid A, and interleukin-6) and attenuated indicators of mononuclear cell activation (168). Exenatide ER has also been reported to decrease levels of brain natriuretic peptide (BNP), CRP, and plasminogen activator inhibitor-1 (PAI-1) (25). Additionally, exenatide BID and metformin yielded a similar improvement in biomarkers of cardiovascular disease and inflammation (e.g., VCAM-1, CRP) in obese participants with prediabetes (169,170). Liraglutide significantly decreased BNP and PAI-1 over

14 weeks (171) and significantly reduced asymmetric dimethylarginine, E-selectin, and PAI-1 when added to metformin monotherapy for 12 weeks (172).

Preliminary studies have also found that GLP-1 RAs may improve endothelial function and impact the development of atherosclerosis in participants with impaired glucose tolerance or T2DM (173). In a study of individuals with impaired glucose tolerance or newly diagnosed T2DM (N = 28), peripheral arterial tonometry demonstrated that a single dose of exenatide significantly improved postmeal endothelial function compared with placebo (173). Additionally, an observational study of endothelial function, as assessed by flow-mediated vasodilation, revealed greater improvement in endothelial function with exenatide compared to glimepiride in patients with T2DM after 16 weeks (174). Again, by comparison, exenatide BID and metformin yielded a similar improvement in endothelial function in obese patients with prediabetes (170). Treatment with liraglutide over 12 weeks did not decrease arterial stiffness in patients with T2DM, but did significantly increase retinal endothelial response (172). More recently, B-mode real-time ultrasound revealed significantly decreased carotid intima-media thickness (IMT) following 4 months of liraglutide treatment in patients with T2DM (175). The IMT changes did not correlate with changes in body weight, fasting glucose, or A1C (175).

GLP-1 RAs may also have potential benefits for use in patients with established cardiovascular disease based on preliminary studies. For example, Lønborg et al demonstrated that exenatide administration within 2 hours of ischemia onset, but not after 2 hours, was associated with significantly smaller infarct size in patients with ST segment elevation myocardial infarction (STEMI) treated with primary percutaneous coronary intervention (176,177). However, despite this improvement, there was no measurable benefit on left-ventricular ejection fraction at 3 months or on clinical outcomes (e.g., cardiac death, myocardial infarction, stent thrombosis, or stroke) at 30 days for patients who received exenatide within 2 hours of ischemia onset compared to those with >2 hours of ischemia prior to exenatide administration (176,177). Exenatide has also been assessed in patients with congestive heart disease (N = 20) (178). Intravenous infusion of exenatide for 6 hours significantly improved cardiac index and pulmonary capillary wedge pressure compared with placebo, but 45% of participants experienced adverse events. Nausea/vomiting was experienced by 6 patients, and heart rate increased in 2, although no adverse events were serious (178).

Taken together, the findings of the studies described above indicate that GLP-1 RAs may act through a number of mechanisms to positively impact cardiovascular status in

Fig. 7. Lipid Changes: Head-to-Head GLP-1 RA Trials (32,33,35).BID, twice daily; DURATION, Diabetes Therapy Utilization: Researching Changes in A1C, Weight and Other Factors Through Intervention With Exenatide Once Weekly; ER, extended release; EXN, exenatide; GLP-1, glucagon-like peptide-1; HDL-C, high-density lipoprotein cholesterol; LEAD, Liraglutide Effect and Action in Diabetes; LIRA, liraglutide; LDL-C, low-density lipoprotein cholesterol; RA, receptor agonist; TC, total cholesterol; TRIG, triglyceridesa Change from baseline; b No statistical analysis; c Significantly different vs EXN BID.


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patients with T2DM. Additionally, the GLP-1 RAs may have potential as interventional agents in patients with established cardiovascular disease. Analyses of clinical trial results and insurance claim databases indicate no increased risk of cardiovascular events as well as a possible benefit in patients with diabetes. However, long-term randomized, controlled, multicenter studies are needed to validate and confirm these findings. Such studies are underway, with results for exenatide and liraglutide expected in 2017 and 2016, respectively (179,180).

What does recent evidence reveal regarding weight loss with GLP-1 RAs?

GLP-1 RAs are not currently approved by the U.S. FDA for weight management. However, weight loss is a prominent clinical characteristic of GLP-1 RA therapy. In a recent meta-analysis of 20- to 52-week trials in subjects with baseline weight of 82-111 kg, mean weight loss was greater with GLP-1 RA therapy compared with control groups (treatment difference, −2.9 kg) (148). These results are consistent with those from head-to-head clinical trials, in which weight loss was similar with liraglutide compared to exenatide BID and with exenatide ER compared to exenatide BID (32,33,148). However, liraglutide produced significantly greater weight loss than exenatide ER in a 26-week head-to-head trial (−3.6 kg and −2.7 kg, respectively; P<.001) (35,36). Data from clinical trials also indicate that approximately 75-80% of individuals treated with exenatide

BID, exenatide ER, or liraglutide lose weight (32.33). Furthermore, sustained weight loss has been demonstrated in several studies (55,57,181). Although not all of the patients who began these trials completed them, the studies demonstrated sustained weight loss for significant numbers of patients with T2DM treated with GLP-1 RAs for up to 4 years.

Gastrointestinal adverse effects are common with GLP-1 RAs, but significant weight loss has also been shown to occur in their absence. In 26- and 30-week trials, significant weight reductions of −2.25 kg, −3.1 kg, and −3.4 kg were reported for liraglutide 1.8 mg, exenatide ER, and exenatide BID, respectively, in patients who did not experience gastrointestinal adverse effects (33,182). By comparison, modestly greater weight reductions of −3.38 kg, −5.4 kg, and −4.1 kg were reported for liraglutide 1.8 mg, exenatide ER, and exenatide BID, respectively, in patients who did experience gastrointestinal adverse effects (33,182). Results from an 82-week exenatide BID clinical trial completer cohort also support the idea that weight loss with GLP-1 RAs is not primarily due to nausea, because weight loss was similar across degrees of nausea and was progressive despite stable nausea (183).

In comparison with other agents, exenatide ER and metformin produced similar weight loss (−2.0 kg) in a 26-week head-to-head trial, and a recent meta-analysis of 7 phase 3 clinical trials demonstrated that participants treated with liraglutide lost a significantly greater percentage of weight than those treated with a thiazolidinedione,

sulfonylurea, insulin glargine, or sitagliptin (22,182). A number of trials have demonstrated comparable glycemic control, but weight loss was experienced in patients treated with GLP-1 RAs compared to weight gain in patients treated with insulin (Fig. 3) (51,53,54,58,59).

Background therapy may impact the degree of weight loss achieved with GLP-1 RAs. In a pooled analysis of clinical trial data, efficacy and safety outcomes for exenatide BID were assessed according to background therapy (65). Background therapy categories included diet and exercise, metformin only, sulfonylurea only, thiazolidinedione only, metformin and sulfonylurea, metformin and thiazolidinedione, and insulin glargine with oral antihyperglycemic agents. Significant weight loss from baseline was achieved with exenatide BID in all background therapy categories except when thiazolidinedione was administered alone (65). Weight loss (−0.6 kg) was reported in the thiazolidinedione-only group, although the number of patients in the group was small (n = 33) (65). It is interesting to note that the addition of exenatide BID to insulin glargine also resulted in significant weight loss from baseline (−1.6 kg; P<.001) (75). A similar result was reported in a small study of exenatide BID or liraglutide added to insulin therapy, although with apparently greater mean weight loss of approximately −7 kg (P<.001), and a retrospective chart review revealed weight loss of −2.5 kg (P = .001) 24 months after exenatide BID was added to insulin glargine (184,185). In 2 studies in which insulin was added after a GLP-1 RA, insulin detemir to liraglutide, or insulin glargine to exenatide BID, participants experienced minor weight loss (−0.16 kg) or no weight gain (76,185).

Weight loss associated with GLP-1 RAs may also be beneficial in patients with nonalcoholic fatty liver disease (NAFLD). (GLP-1 RAs are not currently approved by the U.S. FDA for the treatment of NAFLD). NAFLD is the most common liver condition associated with T2DM (186). The prevalence of NAFLD in diabetes is estimated to range from 34% to 74%, but increases to nearly 100% when both diabetes and obesity are present (186). NAFLD can progress to nonalcoholic steatohepatitis (NASH), which is diagnosed based on histologic findings of hepatic steatosis plus lobular inflammation, hepatocellular ballooning, or fibrosis, and eventually progresses to cirrhosis (187,188). A low liver-to-spleen attenuation ratio may be indicative of hepatic steatosis, with an increased ratio indicating reduced steatosis (189). In a subset of patients in the LEAD-2 trial, treatment with liraglutide 1.8 mg increased the liver-to-spleen attenuation ratio, suggesting improvement in NAFLD/NASH (189). There was a tendency toward a correlation between the improved attenuation ratio and weight loss, and reductions in alanine aminotransferase (ALT) and aspartate aminotransferase (AST) were also noted (189). In a separate study (N = 21), patients treated with

Fig. 8. Increased Risk of Cardiovascular Events and Death in Patients With Severe Hypoglycemia (162,164).ADVANCE, Action in Diabetes and Vascular Disease: Preterax and Diamicron Modified Release Controlled Evaluation; CI, confidence interval; CV, cardiovascular; VADT, Veterans Affairs Diabetes Trial


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pioglitazone had a significant reduction in hepatic fat content (as assessed by magnetic resonance spectroscopy), ALT, and AST from baseline (190). However, treatment with pioglitazone and exenatide BID led to a significantly greater reduction in hepatic fat content and ALT levels (190). Therefore, although the data are still preliminary, GLP-1 RAs may benefit patients with NAFLD or NASH.

Although weight loss is not presently an FDA-approved indication for GLP-1 RAs, it has also been reported in individuals who do not have diabetes. In a study of 152 obese individuals without diabetes treated with lifestyle intervention and exenatide BID or placebo for 24 weeks, exenatide BID generated a significantly greater weight loss (−5.1 kg) compared to placebo (−1.6 kg; P<.001) (191). Similarly, an analysis of a group of 268 obese individuals where <4% had diabetes and who were treated with lifestyle intervention and liraglutide 3 mg/d (which is not presently an approved dose) or orlistat for 104 weeks, weight loss was significantly greater in patients treated with liraglutide (−5.3 kg) compared to orlistat (−2.3 kg) (192). Interestingly, a greater decrease in fat tissue (−15.4%) compared to lean tissue (−2%) was also noted at 20 weeks in this study (192). Moreover, in addition to weight loss, GLP-1 RA treatment also resulted in conversion of substantial numbers of participants who had prediabetes to normal glucose tolerance (Fig. 10) (191,192).

The results of the Satiety and Clinical Adiposity – Liraglutide Evidence in Non-Diabetic and Diabetic Subjects (SCALE)-Maintenance study, which was one of several studies in a series to assess the effects of liraglutide on weight loss, were presented at the American Diabetes Association’s 72nd Scientific Sessions in 2012 and are available online at http://www.clinicaltrials.gov (193,194). The SCALE-Maintenance study was a large, phase 3 trial to assess whether liraglutide 3.0 mg/d (a dose that is not currently approved for the treatment of diabetes) could benefit obese individuals without diabetes who had lost ≥5% body weight with a low-calorie diet and exercise by (1) improving weight loss maintenance over 1 year compared with diet and exercise alone, and (2) further reducing body weight beyond that achieved by a low-calorie diet and exercise (194). Participants (N = 422) who lost ≥5% of their screening weight during a 4- to 12-week prerandomization and run-in period were randomized to receive liraglutide 3.0 mg/d or placebo and were instructed to adhere to an energy-restricted diet for 56 weeks; the study ended with a 12-week treatment-free follow-up period (193). Baseline body weights were 106.7 kg and 105.0 kg for the liraglutide 3.0 mg and placebo groups, respectively (193). Corresponding BMIs were 38.2 kg/m2 and 37.9 kg/m2, and mean weight change from randomization was −5.7 kg in the liraglutide group compared to 0.16 kg in the placebo group (P<.0001) (193). In addition,

significantly more participants maintained their run-in weight loss for 1 year in the liraglutide group compared with the placebo group (81% vs. 49%, respectively; P<.0001), and significantly more participants in the liraglutide group lost ≥5% additional weight (51% vs. 22%, respectively; P<.0001) (193). At week 68 after the 12-week treatment-free follow-up, weight change from randomization was −3.83 kg for the liraglutide group and 0.41 kg for the placebo group (P<.0001) (195). Liraglutide 3.0 mg was generally well tolerated and presented no major safety concerns in this trial (193). In addition, the investigators observed that the numbers of psychiatric events were similar between groups, there were no reports of C-cell hyperplasia or MTC, and no cases of acute pancreatitis were reported.

In another weight loss study in patients without diabetes (N = 41), the mean weight change with 16-week exenatide BID treatment and no additional lifestyle changes resulted in significantly greater weight change compared to placebo (−2.5 kg vs. 0.43 kg, respectively; P<.01) (195). Additionally, the investigators were able to identify 3 patient subgroups within 2 weeks of treatment initiation: high responders (30% of the population) who lost >5% body weight, moderate responders (39% of the population) who lost <5% of their body weight, and nonresponders (31% of the population) who had weight gain or no weight loss. Weight change in these 3 categories was −7.49 kg, −1.91 kg, and 1.70 kg, respectively, with significant differences between the high responders and each of the other 2 groups (195). Significant weight loss and BMI reduction have also been reported in a pilot study of 12 pediatric patients (aged 9-16 years) with extreme obesity treated in a crossover study for 3-month periods of lifestyle

modification with exenatide BID or lifestyle modification alone (196). Reductions in weight (−1.0 kg) and BMI (−0.9 kg/m2) with exenatide BID were significantly different from the weight gain (3.0 kg; P = .02) and increased BMI (0.8 kg/m2; P = .01) that was experienced with placebo. However, there was a slight increase in AST (3.29 U/L) compared to placebo (−3.7 U/L, P<.001) (196). These studies highlight the potential impact of GLP-1 RAs on weight in populations other than those with diabetes.

Weight loss of 5% to 10% or no weight gain is a therapeutic goal for patients with diabetes (28). Weight loss associated with GLP-1 RAs may help many treated patients move closer to achieving their goals. Although the exact mechanisms have not been clearly delineated, it is likely that GLP-1 RAs mediate weight loss in a number of ways, including slowed gastric emptying and decreased appetite/increased satiety. Data from additional studies also suggest that the weight loss effects of GLP-1 RAs may be relevant in other clinical settings, such as weight loss in patients without diabetes, normalizing glucose levels in prediabetes, decreasing NASH, and treating obesity in pediatric patients, although careful and detailed clinical trials will be required to be able to move these concepts into useful patient treatment approaches.

What does recent evidence reveal regarding patient-reported outcomes (PROs) and clinical use of GLP-1 RAs?Importance of PROs

The FDA and National Institute for Clinical Excellence (NICE) have incorporated PROs into their decision process (197). For example, the FDA advises use of a PRO instrument “…when measuring a concept

Fig. 9. Hypoglycemia With GLP-1 RAs: Monotherapy or With Metformin (22,25,45,50,56,165).BID, twice daily; ER, extended release; EXN, exenatide; GLIM, glimepiride; GLP-1, glucagon-like peptide-1; LIRA, liraglutide; MET, metformin; NS, not significant; PBO, placebo; PIO, pioglitazone; RA, receptor agonista EXN BID 10 µg, LIRA 1.8 mg, EXN ER 2.0 mg; b Severe hypoglycemia during insulin infusion as part of substudy procedure.


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best known by the patient or best measured from the patient perspective” (198). Common examples include symptoms, signs, or functionality in the context of disease status (198). Generally, PRO measures reflect the patient’s perspective regarding disease impact on health, functioning, and quality of life, which are concepts that should be incorporated into routine clinical decision making (197,198). In the context of finite care resources, PROs may also provide useful insight regarding the potential impact of an intervention beyond traditional clinical outcomes (197). The importance of patient perspectives in disease management is pronounced in T2DM, which requires considerable patient involvement with a healthcare team and in daily decision making for successful outcomes. Recognition of the importance of patient perspectives is exemplified in the Diabetes Attitudes, Wishes and Needs (DAWN) study, which was designed, in part, to identify patient perspectives and improve psychosocial management of diabetes (199-202). PROs from clinical studies may be helpful for clinicians in ascertaining patient preferences for antihyperglycemic agents by serving as a starting point for a discussion of common concerns. However, they should not preclude discussion with individual patients, whose preferences may differ from those that are commonly expressed.

GLP-1 RAs in the context of patient preferences for characteristics of antihyperglycemic agents

Reductions of 1% in A1C, weight loss, and low risk of hypoglycemia are characteristics of GLP-1 RAs that were first identified by Jendle et al as patient-preferred attributes of antihyperglycemic agents (203). However, patients with diabetes may require

extra encouragement to accept a therapy that requires subcutaneous administration or that is associated with nausea or weight gain (203,204). Providing specific information regarding these characteristics as they pertain to GLP-1 RAs may reassure patients by addressing concerns and providing reasonable expectations (205).

When introducing a GLP-1 RA, it is important to emphasize that the injection is relatively painless because a small, fine needle is used and because it is administered subcutaneously, therefore making it less painful than an intramuscular injection (205).

It is also helpful to introduce the patient to the injection device and, if possible, to attempt a trial injection before leaving the office (205). Injection devices for the currently marketed GLP-1 RAs are depicted in Figure 11. Patients should be advised regarding the possibility of injection site reactions and nodules (16-18). Injection site reactions have been reported with exenatide BID and liraglutide, but are not considered a common adverse effect. However, both are common with the administration of exenatide ER, occurring in ≥5% of patients (16-18). Additionally, it is important to identify a dosing regimen consistent with the patient’s lifestyle. Available GLP-1 RAs offer considerable flexibility in this regard, as options are available for twice-daily, once-daily, and once-weekly dosing (16-18).

Gastrointestinal effects are the most common adverse effects associated with GLP-1 RAs (16-18). Analyses indicate that nausea is reported by 10% to 50% of patients receiving a GLP-1 RA (129,130,206). By comparison, 7% to 26% of patients experience nausea with metformin (101). Patients should be counseled that nausea is likely to be mild and resolve in a few weeks (205). Notably, nausea resolved more quickly with liraglutide, which is the longer-acting agent (32). Moreover, in head-to-head trials, the proportion of patients experiencing nausea was lower with the longer-acting GLP-1 RAs, liraglutide and exenatide ER, compared with exenatide BID (32-34). However, gastrointestinal adverse effects were more common with liraglutide than exenatide ER, with 21% and 9% of study participants reporting nausea, respectively (35). It is also important to recognize that the patient’s experience of nausea may actually reflect “fullness,” and therefore behavioral changes,

Fig. 10. Conversion From Prediabetes to Normal Glucose Tolerance With GLP-1 RAs (191,192).BID, twice daily; BL, baseline; EXN, exenatide; GLP-1, glucagon-like peptide-1; LIRA, liraglutide; ORL, orlistat; PBO, placebo; pts, patients; RA, receptor agonista Prediabetes defined as impaired glucose tolerance or impaired fasting glucose; b 52% to 62%, depending on starting group.

Fig. 11. GLP-1 RA Injection Devices (16-18).BID, twice daily; ER, extended release


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such as decreased portion sizes and reduced fat content at meals, may alleviate symptoms (205). More gradual dose titration may also minimize nausea (205,207).

Gastrointestinal effects associated with GLP-1 RAs are generally transient and mild to moderate in severity. In contrast, severe abdominal pain with or without nausea is symptomatic of acute pancreatitis (16-18). Patients with diabetes are at increased risk of developing acute pancreatitis relative to individuals without diabetes, even after controlling for risk factors such as hypertriglyceridemia and obesity (113-115). It is not clear whether incretin-based therapies, including GLP-1 RAs and DPP-4 inhibitors, increase this risk (8,9,16-18). However, in general, it is advisable to counsel patients with diabetes regarding the potential occurrence of pancreatitis, and they should be encouraged to report severe and/or persistent gastrointestinal pain or upset to their clinician (16-18).

PROs for GLP-1 RA head-to-head comparisonsAlthough the administration of GLP-1

RAs had characteristics rated as less desirable in the study by Jendle et al (i.e., subcutaneous administration, nausea) (203), they generally compare favorably with other agents in terms of treatment satisfaction and their effects on health-related quality of life (HRQL). A willingness to pay approach was also applied using results of trials from the LEAD clinical development program, which included head-to-head comparisons of liraglutide and other antihyperglycemic agents (204). Participants identified that they would be willing to pay more for liraglutide compared to rosiglitazone, glimepiride, or insulin, which was based largely on the weight loss that occurred with liraglutide in contrast to weight gain induced by the other agents. In addition, participants were willing to pay more for liraglutide than exenatide BID based on differences in administration (i.e., administration once daily at any time of the day with liraglutide vs. twice daily at meals with exenatide BID) (204).

GLP-1 RAs also fared well against other agents in head-to-head trials that incorporated PROs. For example:

• Exenatide BID and insulin glargine resulted in comparable improvements in treatment satisfaction and HRQL (208)

• Liraglutide was associated with significantly better HRQL and weight assessment as well as concern, mental and emotional health, and general perceived health compared to glimepiride (all P<.05) (209)

• Treatment satisfaction was greater with liraglutide compared to sitagliptin (P = .03), and convenience of treatment (oral vs. injection) was comparable for the 2 agents (21)

• Exenatide ER resulted in a significantly better improvement in weight-related

quality of life than pioglitazone (P≤.05) (210)

• Exenatide ER and sitagliptin had comparable improvements in weight- related quality of life, HRQL, and treatment satisfaction (210)

• Patients had higher treatment satisfaction following the addition of a GLP-1 RA (exenatide BID or liraglutide) to a treatment regimen that included insulin (184)

In addition, improvement in overall treatment satisfaction was generally greater with longer-acting GLP-1 RAs compared with exenatide BID in head-to-head trials (211,212). Both exenatide BID and exenatide ER were associated with statistically significant (P<.001) and clinically meaningful improvements (≥0.5 standard deviation units) from baseline to week 30 in the Diabetes Treatment Satisfaction Questionnaire-status (DTSQ-s) total score and the Impact of Weight on Quality of Life-Lite (IWQOL-Lite) score (211). Between-group differences in DTSQ-s total and IWQOL-Lite scores were not statistically different, although improvement in the domains of perceived hyperglycemia frequency and willingness to continue treatment were significantly greater with exenatide ER (211). At week 30, patients who switched from exenatide BID to exenatide ER reported a significant improvement in the DTSQ total treatment satisfaction, treatment convenience, treatment flexibility, and satisfaction with continuing treatment scores as well as scores in the IWQOL-Lite physical function and public distress domains (P<.05 for each) (211). Over 26 weeks of treatment, liraglutide was associated with a significantly greater increase in DTSQ-s total score than exenatide BID (P<.0001), reflecting a significant improvement in 7 of 8 domains (current treatment satisfaction, convenience, flexibility, recommendation of current treatment, continuing with current treatment, perceived hyperglycemia, and perceived hypoglycemia) (212). Overall treatment satisfaction also increased significantly from weeks 26 to 40 in patients who switched from exenatide BID to liraglutide (P = .0026), reflecting a significant improvement in convenience and desire to continue (212).

PROs have provided valuable information for clinicians regarding the use of GLP-1 RAs. They have identified characteristics that may pose barriers to patient acceptance of agents in this class (e.g., administration by injection, nausea). As a consequence, clinicians can be prepared to educate patients regarding these characteristics, thereby potentially promoting initiation and adherence. However, such measures have also clearly identified GLP-1 RAs as therapeutically useful despite the necessary injection, which is apparently not a significant barrier to their usage by patients with diabetes. They have also identified patient

satisfaction with treatment despite the potential for gastrointestinal adverse effects. Furthermore, in clinical trials assessing PROs for GLP-1 RAs and other agents, GLP-1 RAs have been associated with improvements in treatment satisfaction and HRQL, indicating that patients are generally satisfied with these agents.

SUMMARYGLP-1 RAs are pleiotropic agents

with distinct clinical profiles. They provide significant improvement in glycemic control across the progression of T2DM, even in combination with basal insulin, although only exenatide BID and liraglutide are currently FDA approved for use in combination with insulin. In clinical trials, improvements in fasting glucose and A1C levels were greater with the longer-acting GLP-1 RAs, liraglutide and exenatide ER, than with exenatide BID, although exenatide BID is likely to have advantages for patients who primarily require improvement in postprandial glucose levels. Switching from exenatide BID to a longer-acting GLP-1 RA has been demonstrated to further improve glycemic control and may be a reasonable option in patients who do not adequately respond to exenatide BID. In addition, adherence to once-daily or once-weekly injections may be greater than that to twice-daily administration, suggesting another rationale for use of the longer-acting agents.

Prescribing information for all 3 GLP-1 RAs includes precautions regarding the potential risk of pancreatitis and acute renal failure. Although no direct or causal link to incretin agents has been identified at this time, clinicians and patients should be aware of the potential risks and of signs and symptoms of these conditions. Prescribing information for exenatide ER and liraglutide also includes precautions regarding a potential risk of MTC. Although the relationship, if any, between the observations in rodents, which prompted the label statements, and any potential risk in humans is unknown, patients should be aware of these precautions. Certainly, these agents should not be prescribed for patients with preexisting medullary C-cell cancer or with a personal or family history of MEN 2.

Preliminary analyses of clinical trial data and analyses of insurance claims database information do not indicate an increased risk of cardiovascular events with GLP-1 RAs, and beneficial effects on nonglycemic end points, such as blood pressure, lipids, and weight, are consistent with these results. However, long-term randomized multicenter trials are currently underway to verify the results of the cardiovascular safety analyses.

Weight loss is a characteristic associated with GLP-1 RAs. A majority of patients lose weight on GLP-1 RAs, and significant weight loss occurs in the absence of gastrointestinal adverse effects. Furthermore, weight loss has been observed with GLP-1 RAs in patients who do not have diabetes.

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Although the need for administration by injection and the potential for adverse gastrointestinal effects are perceived by some as negative characteristics of this class, PROs suggest that other characteristics of GLP-1 RAs, such as glycemic control efficacy, weight loss, and low risk of hypoglycemia, are valued by patients with diabetes. Furthermore, GLP-1 RAs compare favorably with other agents with regard to improvements in treatment satisfaction and HRQL. Overall, recent data continue to support GLP-1 RAs as safe and effective options for the management of hyperglycemia in T2DM.

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Current Issues in GLP-1 Receptor Agonist Therapy for Type 2 Diabetes