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A Critical Analysis of Clinically Available Somatostatin Analog Formulations for Therapy of Acromegaly

Department of Endocrinology (R.D.M.), Leeds Teaching Hospitals National Health Service Trust, Leeds LS9 7TF, United Kingdom; and Department of Medicine (S.M.), Cedars Sinai Medical Center, University of California Los Angeles School of Medicine, Los Angeles, California 90048

Address all correspondence and requests for reprints to: Dr. Shlomo Melmed, Academic Affairs, Room 2015, Cedars Sinai Medical Center, 8700 Beverly Boulevard, Los Angeles, California 90048. E-mail: melmed{at}csmc.edu.

	Abstract

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
Context: Short and long-acting somatostatin (SRIF) analogs are approved for clinical use in acromegaly. Recent analysis of the relative efficacy of octreotide LAR and lanreotide SR on the GH-IGF-I axis in acromegaly favored octreotide LAR in the secondary treatment of patients not preselected by SRIF responsiveness. A novel aqueous formulation of lanreotide, lanreotide Autogel (ATG), has recently been approved and is the predominant (and only in the United States) formulation of lanreotide used clinically.

Objective: We performed a critical review of SRIF analog treatment to establish the relative efficacy of three clinically available SRIF analog preparations, octreotide LAR, lanreotide SR, and lanreotide ATG (Somatuline depot in the United States) in control of the GH-IGF-I axis in acromegaly.

Data Sources: Data were drawn from MEDLINE and the bibliography of analyses of long-acting SRIF analogs.

Data Collection: We reviewed the largest studies of sc octreotide, octreotide LAR, and lanreotide SR, all that included biochemical end-point data for lanreotide ATG, and studies that directly compared the efficacy of octreotide LAR and lanreotide SR.

Data Synthesis: Caveats considered included differences in baseline GH and IGF-I values, patient selection, and interassay and intraassay variability, confounding the analysis. Studies comparing patients treated contiguously with lanreotide SR and octreotide LAR are fraught with methodological problems, however, are suggestive of marginally greater efficacy in control of the GH-IGF-I axis for octreotide LAR. Lanreotide ATG shows noninferiority to lanreotide SR. Five small studies directly comparing octreotide LAR and lanreotide ATG suggest no significant differences between these preparations in control of biochemical end-points.

Conclusion: Lanreotide ATG and octreotide LAR are equivalent in the control of symptoms and biochemical markers in patients with acromegaly.

	Introduction

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
Acromegaly is a rare disease resulting from a benign pituitary somatotrophinoma in over 95% of cases (1), and is characterized clinically by excessive skeletal growth, soft tissue enlargement, disability, and shortened life expectancy. Estimates of the excess mortality from epidemiological studies suggest an approximate 2-fold relative risk ascribed primarily to cardiovascular, cerebrovascular, and respiratory disease (2, 3, 4). The most robust determinant of excess mortality is the circulating GH level (2, 5), though some studies have suggested that IGF-I levels may contribute to adverse mortality outcomes (6, 7). Successful management requires aggressive reduction of GH levels to less than 2.5 µg/liter (5 mU/liter) to achieve mortality rates equivalent to the normal population (2, 5).

Therapeutic modalities available to achieve this target include surgery, radiotherapy, and medical therapy. Surgery by a skilled neurosurgeon remains the mainstay of management, especially for small tumors. However, biochemical control is achieved in less than 50% of patients with macroadenomas, but greater than 80% of microadenomas (1). Control of GH and IGF-I levels after radiotherapy occurs over a period of many years and frequently takes more than a decade. Therefore, medical therapy plays a crucial role in a large proportion of patients with acromegaly who fail to be cured by surgery, or during the interim while the effects of radiotherapy are realized. Somatostatin (SRIF) analogs introduced in the mid-1980s have become the mainstay of medical management (1, 8). SRIF analogs have been used with success as primary therapy in which operative intervention is unlikely to be curative or is associated with an unacceptable risk of morbidity and mortality (1, 9, 10).

In this review we have confined comparisons of efficacy of long-acting SRIF analogs in patients with acromegaly to the biochemical control of disease. Relative tumor shrinkage is an important determinant of which SRIF analog is used clinically, however, there are currently no data from studies randomizing patients to different analogs and using tumor shrinkage as a primary end-point. Switch studies are of limited value because tumor shrinkage is greatest when SRIF analogs are used as primary therapy and during the first 3-months treatment.

	SRIF and Octreotide

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
SRIF is widely distributed within multiple organ systems, and plays an important role in regulating hormone release and other physiological functions (11). The two most biologically active SRIF isoforms comprise 14 or 28 amino acids. SRIF action is mediated through five specific receptor subtypes (SSTRs) (1, 2, 3, 4, 5) differentially expressed in a tissue-specific pattern, thereby conferring functional and therapeutic specificity of ligand action (12). Somatotrophs preferentially express SSTR2 and SSTR5 (13, 14, 15), and respond predominantly to SSTR2-binding analogs (16, 17). SSTRs interact with each other (18), indicating complex pituitary cell responsiveness to receptor ligands (19). SRIF analogs also act at the periphery to inhibit GH action (20). Both octreotide and lanreotide exhibit similar affinities for SSTR2 and SSTR5 in vitro, and apparent differences in clinical efficacy discussed in this review, therefore, likely relate to differences in pharmacodynamics and pharmacokinetics of the various formulations.

Recognition that SRIF is the primary physiological negative regulator of pituitary GH release led to investigation of a therapeutic role for SRIF in managing acromegaly. Although SRIF inhibited GH release from somatotrophinomas (21, 22), clinical usefulness was limited due to a half-life of 2–3 min. This therapeutic limitation was eased by the development of the SRIF analog, octreotide, first used in clinical trials in 1984 (23, 24). Two of the largest studies using this peptide were published in the early 1990s (25, 26), and included 189 and 115 patients, respectively. Collectively, these studies suggested that biochemical control of acromegaly with clinical improvement could be achieved in 50–60% of patients using thrice daily sc octreotide (Table 1).

	Long-Acting SRIF Analogs

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

Baldelli et al. (27) and Verhelst et al. (28) studied the efficacy of lanreotide SR in 118 and 66 patients with acromegaly, respectively (Table 1). In both studies patients were switched from sc octreotide to lanreotide SR, and the dose of the latter optimized on the basis of the biochemistry. Overall, lanreotide SR was found to be more efficacious in controlling GH and IGF-I levels than sc octreotide, with 44–77% of patients achieving biochemical targets. The largest two studies of octreotide LAR enrolled 151 and 110 patients with active acromegaly (29, 30) (Table 1). In the first of these studies, Lancranjan and Atkinson (1999) (29) commenced patients on octreotide LAR after 4-wk individualized sc octreotide, whereas in the second study, patients were naive to SRIF analogs (30). Biochemical targets of GH less than 2.5 µg/liter and a normalized IGF-I were achieved in 63–75% of patients. However, of note is that the overall percentage of patients controlled by lanreotide SR and octreotide LAR was not unduly different from that observed in previous studies strictly optimizing the dose of sc octreotide.

A direct comparison of the percentages of patients achieving GH and IGF-I targets at the end of these four relatively large studies suggests that octreotide LAR exhibits greater efficacy than lanreotide SR. However, in the Lancranjan and Atkinson (29) study, all patients were selected on the basis of a significant known prior response to sc octreotide. Therefore, it is likely that this cohort would have responded well to any clinically available long-acting SRIF analog. This interpretation is supported by examining the proportion of patients with suppression of GH less than 2.5 µg/liter when receiving sc octreotide. This proportion was 65.8% in the Lancranjan and Atkinson (29) study in comparison with 34% in the Baldelli et al. (27) study, despite similar treatment protocols when receiving sc octreotide. In the Cozzi et al. (30) study, patients who did not achieve a 20% or greater reduction in GH and/or IGF-I were actively excluded from the study. This exclusion criterion led to a self-fulfilling hypothesis such that the final result of the study reflects only enrolled patients proven to respond to treatment. Given these biases it is pertinent to note that the aforementioned two studies (29, 30) comprised over 50% of the SRIF responsive patients (n = 486) that were analyzed in a recent metaanalysis (35) comparing efficacy of octreotide LAR with lanreotide SR. Therefore, it is likely that these two studies significantly influenced the outcome of that analysis (35).

	Lanreotide SR and Octreotide LAR

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
There has been controversy over the relative efficacy of the two clinically available long-acting SRIF analogs, lanreotide SR and octreotide LAR, in the management of acromegaly. Most available data comparing lanreotide SR and octreotide LAR relate to secondary treatment after surgery or radiotherapy. A recent analysis contained too few published studies of primary therapy using these agents to allow valid comparisons to be made (35). Furthermore, a large proportion of studies include both primary and secondary treatment without stratification of the cohort before analysis. Considering biochemical efficacy, the outcome of this metaanalysis suggested octreotide LAR to have greater efficacy in achieving both GH (54 vs. 48%) and IGF-I (63 vs. 42%) normalization compared with lanreotide SR in "unselected" patients (35). There was no significant difference in achievement of targets for GH and IGF-I in patients selected on the basis of prior sensitivity to SRIF analogs. Furthermore, there was no significant difference in absolute GH (4.1 vs. 5.3 µg/liter) or IGF-I (330 vs. 432 ng/ml) values between "unselected" patients on octreotide and lanreotide SR, respectively. Although not significant, both values were notably lower in the octreotide LAR treated group (35).

There are a number of methodological difficulties inherent to metaanalyses of such complex conditions as acromegaly and involving measurement of biochemical variables. One of the most significant confounding variables is the lack of standardization of GH and IGF-I assays, making comparison of absolute values between studies almost impossible. Furthermore, definition of achievement of biochemical targets is dependent on a robust reference range to establish normative values, which was a concern in earlier studies (9, 25, 26, 36). If we put aside the challenges with the assays, a review of the studies included in the metaanalysis reveals the study populations to be heterogeneous in terms of initial patient entry criteria. Pretreatment GH and IGF-I values impact significantly on the achievement of control with SRIF analogs (10, 26, 30, 37, 38). Although the metaanalysis (35) examined 12 studies of secondary octreotide LAR therapy (10, 29, 30, 39, 40, 41, 42, 43, 44, 45, 46, 47), after stratification for those who were and were not preselected on the basis of SRIF responsiveness, the latter cohort included patients from only two studies (39, 46). In fact, 92% of patients included in the "unselected" cohort were derived from just a single study (39). It is on the basis of these two studies alone, when compared with the more robust lanreotide SR data, that octreotide LAR was reported to be more efficacious in "unselected" patients (35).

There are however a number of studies that have directly compared the efficacy of lanreotide SR with octreotide LAR (Table 2) (39, 44, 45, 46, 48). Four of these studies were small, containing only five to 15 patients (44, 45, 46, 48). Three of these four studies switched patients stabilized on lanreotide SR for at least 6 months to octreotide LAR (44, 45, 46), and the forth compared biochemical control between a group of patients on lanreotide SR with those on octreotide LAR (48). Two studies showed octreotide LAR to result in significantly greater control of GH and IGF-I levels compared with lanreotide SR (45, 46), whereas the further two studies showed no significant difference between treatments (44, 48). However, in the latter two studies, GH and IGF-I levels were moderately lower when the patients were receiving octreotide LAR.

The cumulative data from these studies suggest that octreotide LAR is modestly more efficacious than lanreotide SR in the biochemical control of acromegaly (Table 2). There are two major caveats in the interpretation of these data. First, lanreotide SR was the initial therapy in all studies, and there is evidence derived from some of the largest studies of SRIF analogs to suggest that control of acromegaly may improve with long-term therapy in the absence of dosage change (30, 39). This was exemplified in the Chanson et al. (39) study, in which patients who simply continued lanreotide SR for a further 3 months without dose change showed a decrease in GH and IGF-I levels. Second, many of the aforementioned studies switched patients on lanreotide SR under routine clinical care to octreotide LAR under study conditions and compared efficacy. It is unclear from these studies whether the frequency of lanreotide SR dosing had been optimized before the change in therapy. Despite these caveats the consistent findings of the aforementioned studies, on balance, lend support to the conclusion that octreotide LAR exhibits greater efficacy compared with lanreotide SR in controlling excess GH and IGF-I secretion characteristic of acromegaly.

	Lanreotide Autogel (ATG)

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
Acknowledgment of the limitations of lanreotide SR led to the development of a more prolonged acting formulation of lanreotide, lanreotide ATG (Somatuline depot; Tercica, Brisbane, CA). Lanreotide ATG is a novel formulation of lanreotide acetate within a supersaturated aqueous solution. The combination of hydrophobic and hydrophilic residues, together with the disulfide bridge, leads to self-association of lanreotide molecules when mixed with water and the formation of a homogeneous semisolid gel. This preparation is formulated as a prefilled syringe containing 60, 90, or 120 mg lanreotide, and is administered as a deep sc injection every 4 wk.

Pharmacokinetic and population pharmacodynamic data for lanreotide ATG (49, 50, 51, 52) show mean minimum steady-state lanreotide levels to display a dose-dependent proportional increase (49, 52). Levels of lanreotide after injection of lanreotide ATG reach similar values to lanreotide SR after three to four injections, and in the long-term result in slightly higher steady-state levels (49, 52). Four injections are required to achieve 90% of the long-term steady-state level. A mean serum concentration of 1.13 ng/ml is required to achieve GH values less than 2.5 µg/liter, however, the IC₅₀ is highly variable between patients (49). The overall model is comparable to that observed with octreotide LAR, which shows similar pharmodynamic properties, high interpatient variability, and incomplete GH suppression (53).

In an intention to treat analysis of a 48-wk study of the efficacy of titrated lanreotide ATG, GH (<2.5 µg/liter) and normalized IGF-I levels were achieved in 85 and 43%, symptoms were controlled, and the formulation was well tolerated (54). In 21 patients stabilized on lanreotide ATG, nine showed good control, and 12 suboptimal GH and IGF-I values. Seven of the nine controlled patients had the dose frequency extended from four to six weekly while maintaining GH and IGF-I targets, resulting in an annual cost savings of around $50,000 (55). In the 12 patients with suboptimal control despite lanreotide ATG doses of 120 mg every 4 wk, an increase in frequency to every 3 wk, with the exception of one individual, failed to significantly improve disease control. This study highlights that, similar to previous studies using octreotide LAR (31), the dose interval can be extended in patients in whom biochemical control is obtained without loss of efficacy. In a further study, patients were given the option of continuing to receive their injections from health care professionals or receiving their injections at home, either by self-administration or their partner (56). Local injection tolerability was good for both groups, and safety profiles were similar. Patients/partners administered lanreotide ATG with no detrimental effect on efficacy (56). When taken together, these two studies suggest that the lanreotide ATG formulation may provide a subset of patients the greatly improved convenience of home injection and at a dosing frequency of 6 wk or longer.

	Lanreotide SR and Lanreotide ATG

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
In contrast to the data included in the recent metaanalysis comparing the efficacy of lanreotide SR and octreotide LAR (35), the predominant formulation of lanreotide currently used in clinical practice is lanreotide ATG. Few data concerning this preparation were available when the metaanalysis was performed. Initial studies of efficacy of lanreotide ATG compared relative efficacy with lanreotide SR with the aim of testing the noninferiority of the new formulation (Table 3).

Data concerning the long-term follow-up of patients maintained on lanreotide ATG for a further 2–3 yr after inclusion in the initial multicenter and extension studies are reported for cohorts enrolled at two centers (57, 58) (Table 3). These studies had limited power however, and collectively showed lanreotide ATG to be equally effective in controlling GH levels but to result in lower IGF-I levels and a greater number of patients achieving a normal IGF-I compared with lanreotide SR.

In a multicenter study, 97 patients stabilized on lanreotide SR for a mean duration of 3.1 ± 0.3 yr were changed to an equivalent dose of lanreotide ATG 120 mg at a variable dose frequency for three to five injections (59). Assessment performed one dosing interval after the final dose of lanreotide ATG showed a higher proportion of patients achieving a GH less than 2.5 µg/liter (44 vs. 54%; P = 0.052), but no change in the proportion achieving IGF-I levels considered as normal (55 vs. 56%).

The available data show noninferiority of lanreotide ATG compared with lanreotide SR in terms of efficacy quantified both biochemically and clinically (Table 3). The data suggest lanreotide ATG to have greater efficacy in the control of GH and IGF-I levels, however, the aforementioned studies are plagued by similar design faults to those previously described when comparing octreotide LAR and lanreotide SR, namely: 1) lanreotide SR was administered before lanreotide ATG in all studies, and biochemical improvements frequently occur with time as a result of previous radiotherapy and long-term SRIF analog therapy; 2) it is unclear whether the dose of lanreotide SR had been optimized in patients enrolled in the studies; 3) where lanreotide levels were available, these were higher when being treated with lanreotide ATG and reflected the improvement in GH and IGF-I values, suggesting that improved efficacy may be a dose effect; and 4) lanreotide ATG was given after lanreotide SR in all studies, and, thus, improvements may, in part, reflect improvements in biochemical control as a result of radiotherapy or prolonged medical therapy. Intuitively it can be concluded that by maintaining higher and more constant steady-state lanreotide levels, lanreotide ATG results in improved control of excessive GH and IGF-I secretion in patients with acromegaly while improving convenience for the patient and clinician.

	Octreotide LAR and Lanreotide ATG

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
Five relatively small studies have compared the efficacy of lanreotide ATG (Somatuline depot) to that of octreotide LAR in patients with acromegaly (60, 61, 62, 63, 64) (Table 4). In the first of these studies, seven patients with active acromegaly receiving octreotide LAR 20–30 mg monthly for a mean of 2.8 yr were commenced on lanreotide ATG after a washout period (60). Patients were randomized to receive lanreotide ATG 60, 90, or 120 mg, and thereafter the dose titrated to achieve a GH less than 1.9 mg/liter (5 mU/liter) and an age-normalized IGF-I level. Twenty-four hour GH profiles on the two treatments were remarkably similar, with no differences noted in secretory characteristics when examined by deconvolution analysis (60). Pulsatile (114 ± 30 vs. 130 ± 35 µg/liter·24 h) and total (209 ± 64 vs. 233 ± 77 µg/liter·24 h) GH levels were not different between the octreotide and lanreotide ATG treatment arms. Six weeks after withdrawal of either analog, GH and IGF-I levels showed no treatment-related differences (60).

In a similar study, 12 patients receiving octreotide LAR 20 mg for at least 4 months and who had achieved GH values of less than 10 µg/liter were changed to lanreotide ATG 90 mg for four injections, and thereafter the dose titrated to achieve a GH level less than 2 µg/liter (<5 mU/liter) (62). Two patients withdrew before the end of the study. GH and IGF-I after the initial three lanreotide 90 mg injections were not significantly different from those reported while on octreotide LAR 20 mg (62). Adjustment of the lanreotide ATG dose on the basis of GH levels was undertaken before administration of the fifth dose; in three patients the dose was increased and in two reduced. IGF-I values after three further injections of lanreotide ATG were lower (P = 0.03), and a higher percentage achieved normal IGF-I levels (60 vs. 80%; P < 0.01) (62). In the fourth of the four switch studies (63), 23 acromegalic patients stabilized on octreotide LAR for 6–18 months were switched to lanreotide ATG 120 mg six weekly for four injections after a 3-month washout period. Thereafter, the frequency of lanreotide 120 mg injection was dependent on GH and IGF-I levels for a further two to three doses. GH and IGF-I values while on octreotide LAR were not significantly different from those after either the fixed dose or after titration of lanreotide ATG (63). GH levels less than 2.5 µg/liter and normal IGF-I values were achieved in 43 and 35% of patients, respectively, when on octreotide LAR, and 60 and 41% after titration of lanreotide ATG.

The final study compared octreotide LAR and lanreotide ATG in a randomized cross-over design in 10 patients previously stabilized on octreotide LAR (64). The duration of each treatment arm was 6 months. Individual octreotide LAR doses remained unchanged from those before enrollment in the study, whereas lanreotide ATG doses were 60, 90, or 120 mg for patients who were receiving octreotide LAR at 10, 20, and 30 mg, respectively. Six patients, respectively, achieved target GH levels of less than 0.96 µg/liter on both treatment arms, however, the absolute change in GH levels was significantly greater on octreotide LAR (–0.65 vs. –0.58 µg/liter) (64). Five and six patients achieved normal IGF-I levels while receiving octreotide LAR and lanreotide ATG, respectively. After the study six patients chose to continue on octreotide LAR and four on lanreotide ATG.

All five studies comparing lanreotide ATG with octreotide are relatively small, though collectively show noninferiority of lanreotide ATG compared with octreotide LAR (Table 3). Of note is that three of these five studies assessed the efficacy of lanreotide ATG after only three injections after either initiation of therapy or dose change and, thus, before steady-state levels had been obtained. Secondary end-points of these studies suggest that lanreotide ATG leads to fewer technical problems with injections and possibly a lower incidence of local injection site reactions, though this is not borne out in all studies (64).

	Discussion

Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 
Medical therapy using SRIF analogs has continued to evolve since the initial studies examining effects of SRIF on GH secretion. The introduction of the long-acting SRIF analog, octreotide, in 1984 as a thrice daily parenteral therapy established an undeniably important role for these analogs in the management of acromegaly. Sustained release microparticle formulations of two SRIF analogs, lanreotide SR and octreotide LAR, became available for use in the early to mid-1990s, greatly improving convenience for the patient while allowing stable steady-state levels of these drugs to be maintained. Both preparations require im injection with a dosing frequency of 28 d for octreotide LAR and 7–14 d for lanreotide SR. The former preparation has been associated with needle viscosity during administration, though these are infrequent in Endocrine Units using this preparation regularly. A recent development has been the introduction of a supersaturated aqueous formulation (lanreotide ATG) in a prefilled syringe that requires deep sc administration every 28 d.

The relative efficacy of the three clinically available SRIF analogs has been debated. Overall, octreotide LAR has been suggested to exhibit greater efficacy in achieving GH and IGF-I targets compared with lanreotide SR; however, this was observed only in patients treated after surgery and/or radiotherapy and who had not been preselected on the basis of responsiveness to SRIF analogs. Furthermore, there was no difference in absolute GH and IGF-I values achieved in these individuals. A critical review of studies directly comparing these two preparations (Table 2) indicates that octreotide LAR is moderately more efficacious in controlling the GH - IGF-I axis in acromegaly; however, a number of biases favoring octreotide LAR have unwittingly been introduced to these comparative studies. Biases and limitations of these studies include small patient number and, therefore, limited statistical power, failure to randomize the treatment order of the analogs being compared, incomplete individualization and optimization of the dose of each analog, and an assumption that dosing should be limited to the manufacturer’s recommended regimen.

Lanreotide ATG has advantages over lanreotide SR in the ease of administration, reduced dosing frequency, and maintenance of more stable steady-state lanreotide levels. Few data concerning this formulation were included in the metaanalysis (35), and separate evaluation of this formulation was not performed. Current data suggest that lanreotide ATG, similar to octreotide LAR, may be marginally more efficacious in controlling GH and IGF-I levels in patients with acromegaly compared with lanreotide SR (Table 3). The studies performed are of similar design to those performed when comparing octreotide LAR and lanreotide SR, and are plagued by similar biases, which favor lanreotide ATG. However, it is likely that lanreotide ATG, by maintaining higher and more constant serum lanreotide levels, improves efficacy beyond that of lanreotide SR. Five small studies have compared octreotide LAR and lanreotide ATG, and concluded that these formulations are of equivalent efficacy (Table 4). A more robust analysis is not possible given the limited power of these studies.

To determine precisely the relative efficacy of SRIF analogs on biochemical control in acromegaly will require a randomized double-blind comparative study. The data analyzed here suggest that differences between octreotide LAR and lanreotide ATG are negligible, and to conduct a study with sufficient power to answer this question would require greater subject numbers than reported in the published literature and would, therefore, be unfeasible given the relatively low incidence of acromegaly (65). Although tumor shrinkage is an important clinical effect of SRIF analogs, there are currently no published studies that randomize patients to the currently available SRIF analogs, thereby allowing comparison of their relative effect on tumor shrinkage. A comparison of tumor shrinkage data from different studies incorporating only one analog is subject to the same biases that we have discussed for the biochemical outcomes.

Therefore, the use of currently available formulations in clinical practice will be determined by a pragmatic approach based on individual preference by the patient and clinician. The use of these generally safe long-acting analogs at six to eight weekly dosing intervals, combined with the possibility of self/partner administration, is a potential advantage in a subset of patients.

	Footnotes

 
Disclosure Statement: R.D.M. receives research support from Novo Nordisk and Ipsen, and lecture fees from Novo Nordisk. S.M. receives research support from Novartis and Biomeasures, and lecture fees from Tercica.

First Published Online May 13, 2008

Abbreviations: ATG, Autogel; SRIF, somatostatin; SSTR, specific receptor subtype.

Received January 4, 2008.

Accepted May 2, 2008.

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Top Abstract Introduction SRIF and Octreotide Long-Acting SRIF Analogs Lanreotide SR and Octreotide... Lanreotide Autogel (ATG) Lanreotide SR and Lanreotide... Octreotide LAR and Lanreotide... Discussion References

 

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