Treat Endocrinol 2005; 4 (5): 319-322MEETINGS REPORT 1175-6349/05/0005-0319/$34.95/0

© 2005 Adis Data Information BV. All rights reserved.

Major Endocrinology MeetingsDavid Williamson

Adis International Inc., Yardley, Pennsylvania, USA

1. 87th Annual Meeting of the Endocrine Society, bodyweight. Data supporting the efficacy of exenatide as a single4–7 June 2005, San Diego, California, US agent were also reported from two phase II studies in patients with

type 2 diabetes inadequately controlled with diet and exerciseThe Endocrine Society’s annual meeting this year was held alone or with metformin.[4]

over 4 days at the San Diego Convention Center and attracted awide range of attendees from basic research scientists through to 1.2 Osteoporosis: Bisphosphonates and Beyondclinical practitioners. The meeting this year took the theme ‘Path-

Oral bisphosphonates are effective agents for the treatment ofways to Discovery and Practice’, and included in the programpostmenopausal osteoporosis, although problems with gastrointes-were a number of theme-related symposia and events focusing ontinal tolerability and complicated dosing instructions impose limi-the translation of advances in basic endocrine research into newtations on their use in some patients. Bisphosphonates are seques-therapies for endocrine diseases. Some meeting highlights, partic-tered in bone and thus exhibit sustained antiresorptive activity,ularly developments in drug therapy, are briefly reported here.lending these agents to the development of less frequently admin-

1.1 Glucagon-Like Peptide-1 Analogs: A New Class for istered oral or intravenous formulations with potential advantagesType 2 Diabetes Mellitus of minimizing gastrointestinal effects and improving adherence to

therapy.The glucagon-like peptide-1 (GLP-1) analogs are a new class of

1.2.1 Interim Results from DIVA and MOBILEagents for the treatment of type 2 diabetes mellitus, and exenatideis the first from this class to become available, having recently The ongoing 2-year DIVA (Dosing IntraVenous Administra-been approved and launched in the US. Exenatide mimics the tion) study of ibandronate is assessing 2-monthly and 3-monthlyactions of naturally occurring GLP-1, which is an incretin hor- intravenous regimens. Both were reported to be at least as effec-mone secreted by intestinal cells in response to food intake. It tive as the currently established daily oral regimen based on first-enhances the release of insulin, inhibits glucagon release, in- year results.[5] Efficacy was based on bone mineral density (BMD)creases satiety, and slows gastric emptying, effects that have been and the levels of bone turnover markers. For BMD gains at theshown to translate into improved glycemic control and reduction lumbar spine, both of the intravenous regimens were found to beof bodyweight. superior to the daily oral regimen, and overall safety and tolerabili-

ty profiles were similar for the intravenous and daily ibandronateStudies were presented at the meeting on the long-term use ofregimens. Data from the 2-year MOBILE (Monthly Oral iBan-subcutaneously administered exenatide in addition to oral antihy-dronate In LadiEs) study were also presented, examining threeperglycemic agents, as well as its use as a single agent for type 2different monthly oral ibandronate regimens. The results after 1diabetes. The long-term data were from three separate studies inyear show that monthly administration appears at least equivalentpatients with type 2 diabetes who were also receiving met-in efficacy to daily oral ibandronate, based on comparisons offormin,[1] a sulfonylurea,[2] or both,[3] and showed that patientsBMD and bone turnover markers.[6,7]who received exenatide throughout the study had sustained im-

provements in glycosylated hemoglobin and progressive weight Another issue relating to bisphosphonate therapy is the thresh-reduction. Patients who were randomized to placebo during the old for intervention, and the comparative efficacy of bisphospho-initial 30-week study and switched to exenatide treatment at the nates in patients with different BMD T-scores. In a study investi-beginning of the 52-week extension had similar reductions in gating the antifracture efficacy of risedronate in postmenopausalglycosylated hemoglobin to those who received exenatide women, benefits were found to be independent of baselinethroughout the 82 weeks, with accompanying reductions in BMD.[8] The data were derived from four phase III placebo-

320 Williamson

controlled studies that included 2575 postmenopausal women 1.3 Optimizing Growth Hormone Therapytreated with a bisphosphonate for up to 3 years.

Several interesting developments in the delivery of growthhormone therapy were covered in sessions at the conference,1.2.2 Other Therapeutic Approachesamong them reports of insulin-like growth factor-1 (IGF-1)-basedIn a basic research/clinical interface symposium, several poten-dosing of growth hormone in children, and progress with newtial therapeutic approaches to osteoporosis were discussed.sustained-release and inhaled formulations.

The molecular actions of vitamin D and aspects of potency,A study was presented, in the clinical trials session, on the

efficacy, and selectivity of vitamin D analogs were discussed byoptimization of growth hormone therapy in children using dose

Dr John Pike from the University of Wisconsin-Madison, Wiscon-adjustment according to IGF-1 levels.[9] Levels of IGF-1 correlate

sin, US. In particular, a new analog, 2MD, displays a potency ofwith response to growth factor, but there are large variations in

action that is 2–3 log greater than that of vitamin D. The super-individual IGF-1 responses when conventional weight-based dos-

agonist-like properties of this analog appear to be due to the facting is used. This is important both in terms of gaining an adequate

that structurally it does not bind to vitamin D binding protein. InIGF-1 response to administered growth hormone and in avoiding

animal studies, 2MD has demonstrated profound effects on boneexcessively high levels of IGF-1. In this study in children with

formation, bone strength, and BMD, and may have future potentialgrowth hormone deficiency or idiopathic short stature (ISS), indi-

as an anabolic agent for the treatment of osteoporosis.vidualizing growth hormone doses by targeting to higher (+2

The importance of RANKL (receptor activator of nuclear factorstandard deviations) IGF-1 levels, rather than to mean IGF-1

kappa B ligand) in the regulation of osteoclast differentiation andlevels, was found to increase growth by 45% in children with

function was discussed by Dr Michael McClung from the Provi-growth hormone deficiency and by 58% in children with ISS.

dence Medical Center and Oregon Osteoporosis Center in Port-Efficacy and safety data were reported from a phase II study of

land, Oregon, USA, who also reported some results from clinicala new sustained-release formulation of recombinant human

studies with RANKL-targeted therapy. RANKL, through its acti-growth hormone (LB03002).[10] This study, in children with con-

vation of osteoclasts, plays a central role in disorders of increasedfirmed growth hormone deficiency, compared the sustained-re-

bone resorption, and RANKL inhibition therefore presents a po-lease growth hormone at two different doses with daily recombi-

tential new option for the treatment and prevention of bone loss.nant growth hormone. The increases in height velocity over 6

Data presented on AMG 162, a fully human monoclonal antibodymonths were comparable between the regimens, as were increases

that blocks the binding of RANKL to its receptor, showed rapidin IGF-1 and IGF binding protein-3, and tolerability. Pharmacoki-

and durable reduction of bone resorption. The BMD responsesnetic and safety results were also presented for an inhaled formula-

observed have been typical of those seen with bisphosphonates.tion, somatropin inhalation powder (SIP).[11] The single-dose com-

However, AMG 162 appears more reversible in its effects thanparison study with subcutaneous human growth hormone was

bisphosphonates, which remain in bone for a relatively long periodconducted in 12 healthy adults. SIP delivered therapeutic concen-

of time, and may therefore have a lower risk of oversuppression oftrations of growth hormone, based on pharmacokinetic profiles,

bone turnover.and IGF-1 levels were increased by a mean of 70% from baseline

Finally, an update of progress in the development of selectivelevels. SIP was well tolerated and there were no significant

estrogen receptor modulators (SERMS) and selective androgenchanges in pulmonary function during the study.

receptor modulators (SARMS) was presented by Dr SundeepKhosia from the Mayo Clinic College of Medicine in Rochester, 2. American Diabetes Association 65th ScientificMinnesota, US. Raloxifene is currently the only SERM available Sessions, 10–14 June 2005, San Diego, California, USfor the treatment of osteoporosis, although several others arecurrently undergoing phase III trials, including arzoxifene, The American Diabetes Association (ADA) scientific sessionsbazedoxifene, and lasofoxifene. Clinical trial data will show how followed the Endocrine Society’s annual meeting in San Diego,these compare with raloxifene in terms of their effects on bone as attracting over 12 000 international researchers, clinicians, andwell as other tissues. SARMs, compared with the SERMS, are other health professionals. Sessions covered all aspects of diabe-much less advanced in development, with the first having entered tes, from basic research areas including islet cell biology andphase I trials. Dr Khosia noted that it is likely that initially SERMs insulin mechanisms, through epidemiology and genetics, towill be developed for use in postmenopausal women and SARMs clinical management of diabetes and its complications. There werefor use in aging men, but this may change with increasing under- many interesting presentations relating to new developments instanding of the broader mechanisms of estrogens and androgens. drug therapy, some of which are highlighted here.

© 2005 Adis Data Information BV. All rights reserved. Treat Endocrinol 2005; 4 (5)

ENDO and ADA Meetings Report 321

2.3.1 Glucagon-Like Peptide-1 Analogs2.1 Targeting Cannabinoid Receptors in Obesityand Diabetes A comparative study assessed the potential of exenatide as an

alternative to insulin glargine in patients with type 2 diabetesinadequately controlled with metformin and/or a sulfonylurea.[14]The cannabinoid receptor antagonist rimonabant is a new agentIn this 26-week phase III study, both exenatide and insulinunder development for the treatment of obesity and other riskglargine achieved similar reductions in HbA1c and similar percent-factors contributing to the metabolic syndrome. The RIOages of patients in the two groups achieved HbA1c values below(Rimonabant In Obesity) phase III trial series includes a study7%. Exenatide was associated with a mean weight loss of 2.3kg inspecifically in obese or overweight patients with type 2 diabetesthis study, compared with a mean gain of 1.8kg in the insulin(RIO-Diabetes), results of which were presented in the late-break-glargine group. Exenatide was also more effective in reducinging clinical trials session. In RIO-Diabetes, rimonabant loweredpostprandial glucose excursions and had a lower incidence ofhemoglobin A1c (HbA1c) and produced significant reductions innocturnal hypoglycemia than insulin glargine. As in other studiesbodyweight, waist circumference, and triglyceride levels, with aof exenatide, nausea was a common adverse event, occurring insignificant increase in high-density lipoprotein (HDL)-cholesterol.57% of patients.A significant reduction in the prevalence of the metabolic syn-

drome was also reported among patients who received rimonabant. An analysis of cardiovascular risk factors (triglycerides, totalIt was estimated that more than half of the observed benefits in cholesterol, HDL, low-density lipoprotein, apolipoprotein B, andglycemic control and HDL-cholesterol levels were independent of systolic and diastolic blood pressure) was presented from the threeweight loss. Overall, the clinical improvements were found to be long-term phase III trials of exenatide.[15] Long-term exenatideconsistent with those reported to date from the other trials in the treatment showed sustained improvements in glycemic parame-series (RIO-North America, RIO-Europe and RIO-Lipids). ters, progressive weight reduction, and improvements in lipids and

blood pressure. The improvements seen in cardiovascular riskfactors were seen to be greatest in those patients with the greatest2.2 Dual Peroxisome Proliferator-Activatedweight loss.Receptor Agonists

Another GLP-1 analog CJC-1131 exhibits an extended circula-tory half-life, through its binding to human albumin in vivo. In aSeveral studies of muraglitazar, a dual peroxisome proliferator-12-week study in patients with type 2 diabetes inadequately treat-activated receptor (PPAR) α/γ agonist, were reported at the meet-ed with metformin or a sulfonylurea, the addition of CJC-1131ing. The rationale behind the use of dual PPAR agonists is tosignificantly reduced HbA1c with no increased risk of hypoglyce-combine the PPARγ-mediated effects on glycemic control andmia.[16] Nausea was again a frequent adverse event with an overallinsulin sensitivity with the PPARα-mediated effects on lipid me-incidence of 25% during the first 4 weeks of the study, decreasingtabolism. Results were presented from comparative studies within frequency thereafter.muraglitazar or the thiazolidinedione pioglitazone, as well as long-

term data from an earlier dose-ranging study of muraglitazar inpatients with type 2 diabetes. In the comparative trial, muraglitazar 2.3.2 Dipeptidyl Peptidase IV Inhibitorswas shown to reduce blood glucose levels more effectively than

Natural GLP-1 has a short circulatory half-life, due to itspioglitazone, when each was added to metformin therapy.[12]

proteolytic inactivation by the enzyme dipeptidyl peptidase IVMuraglitazar produced significantly greater reductions in HbA1c(DPPIV). An alternative therapeutic approach to the developmentthan pioglitazone, and more patients achieved the ADA target forof modified GLP-1 analogs, such as exenatide and CJC-1131, isHbA1c. Triglyceride levels were also significantly lower in mura-therefore the development of specific DPPIV inhibitors. A poten-glitazar-treated patients. Another PPAR α/γ agonist, tesaglitazar,tial advantage of DPPIV inhibitors is that they may be adminis-showed similar improvements in glycemic and lipid parameters intered orally. An example of this class of agent is sitagliptinphase II studies presented.[13]

(MK0431), and phase II studies were presented on the use of thisagent as monotherapy or as an adjunct to metformin in patients

2.3 Intense Interest in Incretin-Based Therapies with type 2 diabetes. In a 12-week study, sitagliptin, as a singleagent, produced dose-dependent decreases in fasting plasma glu-

The intense interest in the development of incretin-based thera- cose and HbA1c.[17] Similarly, sitagliptin was reported to be effec-pies for the treatment of type 2 diabetes was also evident in a tive and generally well tolerated when added to existingnumber of studies presented at the ADA meeting. metformin therapy in poorly controlled patients.[18] Sitagliptin

© 2005 Adis Data Information BV. All rights reserved. Treat Endocrinol 2005; 4 (5)

322 Williamson

porosis. 87th annual meeting of the Endocrine Society; 2005 Jun 4–7; Sancaused no significant changes in bodyweight in either of theseDiego (CA): 454-5

studies.8. Lindsay R, Magowan S, Barton I, et al. Risedronate’s antifracture efficacy is

independent of baseline BMD levels [abstract no. OR41-3]. 87th annual meet-

ing of the Endocrine Society: 2005 Jun 4–7; San Diego (CA): 1352.4 Inhaled Insulin: Long-Term Efficacy and Safety

9. Cohen P, Rogol AD, Howard CP, et al. IGF-based dosing optimizes the safety and

efficacy of GH therapy in children with GHD and ISS: results of a randomized

controlled study [abstract no. S41-3]. 87th annual meeting of the EndocrineA number of studies were presented on inhaled insulins. TheSociety; 2005 Jun 4–7; San Diego (CA): 48most advanced of the inhaled insulins in development is Exu-

10. Kim DH, Lee BC, Shin JH, et al. A sustained release human growth hormonebera®,1 and studies were presented on efficacy and tolerability in(LB03002): efficacy and safety following six-month treatment in children with

both type 1 and type 2 diabetes. In patients with type 1 diabetes, growth hormone deficiency [abstract no. OR33-2]. 87th annual meeting of thetherapy over 3 months was reported to be well tolerated and as Endocrine Society; 2005 Jun 4–7; San Diego (CA): 122

effective as subcutaneous short-acting insulin.[19] Long-term data 11. Chipman J, Lucas R, Jackson B, et al. Pharmacokinetic and safety results of a

human single-dose comparison of somatropin inhalation powder vs subcutane-from a number of phase III studies in patients with type 2 diabetesous injection of somatropin [abstract no. OR33-3]. 87th annual meeting of thewere presented, concluding that over a 2-year period, glycemicEndocrine Society; 2005 Jun 4–7; San Diego (CA): 122-3control was maintained and no new safety concerns emerged.[20]

12. Defronzo RA, Rubin CJ, Mohideen P, et al. Improvement of glycemic control withThe results showed that over 2 years, there were no significantmuraglitazar, a novel dual PPAR alpha/gamma agonist, in combination with

changes in parameters of lung function. Insulin antibody levelsmetformin in patients with type 2 diabetes: a double-blind, randomized, piogli-

plateaued in patients between 6 and 12 months in the various tazone-controlled study [abstract no. 14-OR]. Diabetes 2005 Jun; 54 Suppl. 1: 4

studies, and the presence of antibodies was not associated with 13. Goldstein BJ, Rosenstock J, Anzalone D, et al. Tesaglitazar improves glucose and

effects on glycemic control or with adverse events in any of the lipid abnormalities in patients with type 2 diabetes [abstract no. 83-OR].

Diabetes 2005 Jun; 54 Suppl. 1: 21studies.14. Heine RJ, Van Gaal LF, Johns D, et al. Comparison of exenatide and insulin

glargine in MET and SU-treated patients with type 2 diabetes: exenatide

achieved equivalent glycemic control, with weight reduction and less nocturnalReferences hypoglycemia [abstract no. 9-OR]. Diabetes 2005 Jun; 54 Suppl. 1: 3

15. Kendall DM, Kim D, Poon T, et al. Improvements in cardiovascular risk factors1. Kim D, Stonehouse A, Han J, et al. Exenatide (exendin-4) reduced A1C and weightover 82 weeks in metformin-treated patients with type 2 diabetes [abstract]. accompanied sustained effects on glycemia and weight reduction in patients87th annual meeting of the Endocrine Society; 2005 Jun 4–7; San Diego (CA): with type 2 diabetes treated with exenatide for 82 weeks. Diabetes 2005 Jun; 54642

Suppl. 1: 212. Kim D, Zhang B, Mac S, et al. Exenatide (exendin-4) reduced A1C and weight over 16. Ratner RE, Guivarc’h P-H, Dreyfus J-F, et al. Effects of DAC-GLP:1(CJC-1131)

82 weeks in sulfonylurea-treated patients with type 2 diabetes [abstract]. 87thon glycemic control and weight over 12 weeks in metformin-treated patientsannual meeting of the Endocrine Society; 2005 Jun 4–7; San Diego (CA): 642with type 2 diabetes [abstract]. Diabetes 2005 Jun; 54 Suppl. 1: 3

3. Kim D, MacConell L, Nielsen L, et al. Exenatide (exendin-4) reduced mean A1C17. Scott R, Herman G, Zhao P, et al. Twelve-week efficacy and tolerability of MK-and weight over 82 weeks in metformin- and sulfonylurea-treated patients with

0431, a dipeptidyl peptidase IV (DDP-IV) inhibitor, in the treatment of type 2type 2 diabetes. 87th annual meeting of the Endocrine Society; 2005 Jun 4–7;San Diego (CA): 83 diabetes (T2D). Diabetes 2005 Jun; 54 Suppl. 1: 10-11

18. Brazg R, Thomas K, Zhao P, et al. Effect of adding MK-0431 to on-going4. Poon T, Taylor K, Zhuang D, et al. Exenatide monotherapy provides glycemiccontrol comparable to that of exenatide combination therapy in subjects with metformin therapy in type 2 diabetic patients who have inadequate glycemictype 2 diabetes [abstract]. 87th annual meeting of the Endocrine Society; 2005 control on metformin. Diabetes 2005 Jun; 54 Suppl. 1: 3Jun 4–7; San Diego (CA): 642

19. Dumas R, England RD, Riese RJ, et al. Exubera® is well tolerated and achieves5. Civitelli R, Ste-Marie L-G, Seeman E, et al. Efficacy of intermittent intravenous tight glycemic control in patients with type 1 diabetes. Diabetes 2005 Jun; 54

ibandronate injection therapeutically equivalent to daily oral ibandronate inSuppl. 1: 87postmenopausal osteoporosis [abstract no. OR41-2]. 87th annual meeting of the

20. Cefalu WT, Serdarevic-Pehar M, Exubera® phase 3 Study Group. Long-term useEndocrine Society; 2005 Jun 4–7; San Diego (CA): 135

of Exubera® in type 2 diabetes: observations on glycemic control, pulmonary6. Bolognese MA, Kendler D, Drezner M, et al. Efficacy of monthly and daily oralfunction and antibody formation. Diabetes 2005 Jun; 54 Suppl. 1: 88ibandronate is at least equivalent in postmenopausal women with osteoporosis.

87th annual meeting of the Endocrine Society; 2005 Jun 4–7; San Diego (CA):457

Correspondence and offprints: David Williamson, Adis International Inc.,7. Drezner M, Bolognese MA, Kendler D, et al. Once-monthly dosing of oralibandronate is as well tolerated as once-daily dosing in postmenopausal osteo- 770 Township Line Road, Suite 300, Yardley, PA 19067, USA.

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© 2005 Adis Data Information BV. All rights reserved. Treat Endocrinol 2005; 4 (5)