INTRODUCTIONThe clinical features and increased mortality associated with Cushing's syndrome result from a chronic excess of circulating cortisol. As LCI699 potently inhibits 11β-hydroxylase, which catalyzes the final step of cortisol synthesis, it is a potential new treatment for Cushing's disease, the most common cause of endogenous Cushing's syndrome.METHODSAdult patients with moderate-to-severe Cushing's disease (urinary free cortisol [UFC] levels >1.5 × ULN [upper limit of normal]) received oral LCI699 for 10 weeks in this proof-of-concept study. LCI699 was initiated at 4 mg/d in two equal doses; the dose was escalated every 14 days to 10, 20, 40, and 100 mg/d until UFC normalized, whereupon the dose was maintained until treatment ended (day 70). The primary endpoint was UFC ≤ ULN or a ≥50% decrease from baseline at day 70.RESULTSTwelve patients were enrolled and completed the study. Baseline UFC ranged over 1.6-17.0 × ULN. All 12 patients achieved UFC ≤ULN or a ≥50% decrease from baseline at day 70; 11 (92%) had normal UFC levels at that time. After treatment discontinuation (day 84), UFC was >ULN in 10 patients with available measurements. Mean 11-deoxycortisol, 11-deoxycorticosterone, and adrenocorticotropic hormone levels increased during treatment and declined after discontinuation. Mean systolic and diastolic blood pressure decreased from baseline by 10.0 and 6.0 mmHg, respectively. LCI699 was generally well tolerated; most adverse events (AEs) were mild or moderate. The most common AEs included fatigue (7/12), nausea (5/12), and headache (3/12). No serious drug-related AEs were reported.CONCLUSIONSLCI699 was efficacious and well tolerated in patients with Cushing's disease enrolled in this proof-of-concept study.

WSTEP. Celem pracy by³a ocena wp³ywu leczenia wildagliptyn± - inhibitorem dipeptydylopeptydazy- 4 na insulinowra?liwoae oraz czynnoae komorek beta u osob z nieprawid³ow± glikemi± na czczo (IFG). MATERIA£ I METODY. Wildagliptyne w dawce 100 mg podawano doustnie raz na dobe 22 pacjentom z IFG (11 kobiet i 11 me?czyzn, redni wiek ± SD: 59,6 ± 11,5 roku). Badanie prowadzono metod± pojedynczo lepej proby. Uczestnicy badania otrzymywali placebo przez okres 2 tygodni (okres wstepny badania, run-in ), a nastepnie wildagliptyne przez 6 tygodni (okres w³aciwej terapii) i ponownie placebo przez 2 tygodnie (bez aktywnego leczenia - okres wash-out , czyli eliminacji leku). W 2., 8. i 10. tygodniu wykonywano do?ylny test obci±?enia glukoz± z czestym pobieraniem probek krwi (FSIGT), po ktorym nastepowa³ 2-godzinny test obci±?enia standardowym posi³kiem (MIT). Na podstawie FSIGT okrelono natychmiastow± odpowied¼ insulinow± na glukoze (AIRg) oraz wska¼nik insulinowra?liwoci (St) - wyniki te pozwoli³y na obliczenie wska¼nika podatnoci ( disposition index ) (AIRg × S1) jako miary czynnoci komorek beta. WYNIKI. Poziom glikemii na czczo nie zmieni³ sie po 6 tygodniach leczenia wildagliptyn±. Wskutek leczenia redni poziom AIRg ± SEM zwiekszy³ sie z 224 ± 44 pmol/l do 286 ± 52 pmol/l (p < 0,05), a S1 poprawi³ sie z 2,8 ± 0,5 do 3,5 ± 0,5 × 10-5 × min-1 × × pmol-1 (p < 0,01), co spowodowa³o wzrost wska¼nika podatnoci z 688 ± 180 do 1164 ± ± 318 × 10-5/min (p < 0,05). Powy?sze zmiany nie utrzyma³y sie jednak po okresie wash-out . Podczas MTT obszar pod krzyw± sekrecji glukozy by³ istotnie zmniejszony po leczeniu (240 ± 15 vs. 191 ± 14 mmol × l-1 × min-1 (p = 0,002), ale tego efektu rownie? nie obserwowano po okresie wash-out . WNIOSKI. Wildagliptyna - inhibitor dipeptydylopeptydazy-4 - poprawia funkcje komorek beta oraz wra?liwoae na insuline, prowadz±c do obni?enia glikemii poposi³kowej u pacjentow z IFG, o ktorych wiadomo, ?e cechuj± sie dysfunkcj± komorek beta. Tak wiec wildagliptyna mo?e zapobiegaae progresji do cukrzycy u osob z grupy wysokiego ryzyka.

WSTEP. Celem pracy by³a ocena wp³ywu leczenia wildagliptyn± - inhibitorem dipeptydylopeptydazy- 4 na insulinowra?liwo¶ae oraz czynno¶ae komorek beta u osob z nieprawid³ow± glikemi± na czczo (IFG). MATERIA£ I METODY. Wildagliptyne w dawce 100 mg podawano doustnie raz na dobe 22 pacjentom z IFG (11 kobiet i 11 me?czyzn, ¶redni wiek ± SD: 59,6 ± 11,5 roku). Badanie prowadzono metod± pojedynczo ¶lepej proby. Uczestnicy badania otrzymywali placebo przez okres 2 tygodni (okres wstepny badania, run-in ), a nastepnie wildagliptyne przez 6 tygodni (okres w³a¶ciwej terapii) i ponownie placebo przez 2 tygodnie (bez aktywnego leczenia - okres wash-out , czyli eliminacji leku). W 2., 8. i 10. tygodniu wykonywano do?ylny test obci±?enia glukoz± z czestym pobieraniem probek krwi (FSIGT), po ktorym nastepowa³ 2-godzinny test obci±?enia standardowym posi³kiem (MIT). Na podstawie FSIGT okre¶lono natychmiastow± odpowied¼ insulinow± na glukoze (AIRg) oraz wska¼nik insulinowra?liwo¶ci (St) - wyniki te pozwoli³y na obliczenie wska¼nika podatno¶ci ( disposition index ) (AIRg × S1) jako miary czynno¶ci komorek beta. WYNIKI. Poziom glikemii na czczo nie zmieni³ sie po 6 tygodniach leczenia wildagliptyn±. Wskutek leczenia ¶redni poziom AIRg ± SEM zwiekszy³ sie z 224 ± 44 pmol/l do 286 ± 52 pmol/l (p < 0,05), a S1 poprawi³ sie z 2,8 ± 0,5 do 3,5 ± 0,5 × 10-5 × min-1 × × pmol-1 (p < 0,01), co spowodowa³o wzrost wska¼nika podatno¶ci z 688 ± 180 do 1164 ± ± 318 × 10-5/min (p < 0,05). Powy?sze zmiany nie utrzyma³y sie jednak po okresie wash-out . Podczas MTT obszar pod krzyw± sekrecji glukozy by³ istotnie zmniejszony po leczeniu (240 ± 15 vs. 191 ± 14 mmol × l-1 × min-1 (p = 0,002), ale tego efektu rownie? nie obserwowano po okresie wash-out . WNIOSKI. Wildagliptyna - inhibitor dipeptydylopeptydazy-4 - poprawia funkcje komorek beta oraz wra?liwo¶ae na insuline, prowadz±c do obni?enia glikemii poposi³kowej u pacjentow z IFG, o ktorych wiadomo, ?e cechuj± sie dysfunkcj± komorek beta. Tak wiec wildagliptyna mo?e zapobiegaae progresji do cukrzycy u osob z grupy wysokiego ryzyka.

OBJECTIVE - To evaluate the effect of treatment with the dipeptidyl peptidase (DPP)-4 inhibitor vildagliptin on insulin sensitivity and beta-cell function in subjects with impaired fasting glucose (IFG). RESEARCHDESIGN AND METHODS - A total of 22 subjects with IFG (11 female and 11 male, mean +/- SD age 59.6 +/- 11.5 years) were treated orally with 100 mg vildagliptin once daily in a single-blind study. Subjects received placebo for 2 weeks (run-in) followed by vildagliptin for 6 weeks (treatment) and then placebo for 2 weeks (washout). A frequently sampled intravenous glucose tolerance test (FSIGT), followed by a 2-h meal tolerance test (MTT), was performed at 2, 8, and 10 weeks. From the FSIGT, the acute insulin response to glucose (AIR(g)) and insulin sensitivity index (S) were determined and used to compute the disposition index (AIRg X S,) as a measure of beta-cell function.RESULTS - Fasting plasma glucose did not change after 6 weeks of vildagliptin treatment. With treatment, mean +/- SEM AIR(g) increased from 224 +/- 44 to 286 +/- 52 pmol/1(P < 0.05), and S, improved from 2.8 +/- 0.5 to 3.5 0.5 X 10(-5) - min(-1). pmol(-1) center dot 1 (P < 0.01), resulting in an increase in the disposition index from 688 +/- 180 to 1,164 +/- 318 X 10(-5)/min (P < 0.05). These effects were not sustained after washout. During the MTT, the incremental area under the glucose curve was significantly decreased after treatment (240 +/- 15 vs. 191 +/- 14 mmol center dot 1(-1) min-1; P = 0.002), but this effect was not sustained after washout.CONCLUSIONS - The DPP-4 inhibitor vildagliptin improves insulin sensitivity and P-cell function, leading to improved postprandial glycemia in subjects with IFG, who are known to have beta-cell dysfunction. Thus, vildagliptin may prevent progression to diabetes in high-risk subjects.

The Journal of Clinical PharmacologyVolume 47, Issue 1 p. 127-131 Vildagliptin Does Not Affect C-Peptide Clearance in Patients With Type 2 Diabetes Dr Yan-Ling He PhD, Corresponding Author Dr Yan-Ling He PhD Novartis Institutes of Biomedical Research, Cambridge, MassachusettsAddress for correspondence: Yan-Ling He, PhD, DMSc, Exploratory Development, Novartis Institutes of Biomedical Research, 400 Technology Square, Building 605, 8th Floor Rm 811, Cambridge, MA 02139-3584; e-mail: yanling.he@novartis.com.Search for more papers by this authorDr Anne Horowitz PhD, Dr Anne Horowitz PhD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this authorDr Catherine E. Watson PhD, Dr Catherine E. Watson PhD Novartis Institutes of Biomedical Research, Cambridge, MassachusettsSearch for more papers by this authorDr James E. Foley PhD, Dr James E. Foley PhD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this authorDr William Sallas PhD, Dr William Sallas PhD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this authorDr Monica Ligueros-Saylan MD, Dr Monica Ligueros-Saylan MD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this author Dr Yan-Ling He PhD, Corresponding Author Dr Yan-Ling He PhD Novartis Institutes of Biomedical Research, Cambridge, MassachusettsAddress for correspondence: Yan-Ling He, PhD, DMSc, Exploratory Development, Novartis Institutes of Biomedical Research, 400 Technology Square, Building 605, 8th Floor Rm 811, Cambridge, MA 02139-3584; e-mail: yanling.he@novartis.com.Search for more papers by this authorDr Anne Horowitz PhD, Dr Anne Horowitz PhD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this authorDr Catherine E. Watson PhD, Dr Catherine E. Watson PhD Novartis Institutes of Biomedical Research, Cambridge, MassachusettsSearch for more papers by this authorDr James E. Foley PhD, Dr James E. Foley PhD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this authorDr William Sallas PhD, Dr William Sallas PhD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this authorDr Monica Ligueros-Saylan MD, Dr Monica Ligueros-Saylan MD Novartis Pharmaceuticals Corporation, East Hanover, New Jersey.Search for more papers by this author First published: 07 March 2013 https://doi.org/10.1177/0091270006295061Citations: 6Read the full textAboutPDF ToolsRequest permissionExport citationAdd to favoritesTrack citation ShareShare Give accessShare full text accessShare full-text accessPlease review our Terms and Conditions of Use and check box below to share full-text version of article.I have read and accept the Wiley Online Library Terms and Conditions of UseShareable LinkUse the link below to share a full-text version of this article with your friends and colleagues. Learn more.Copy URL Share a linkShare onFacebookTwitterLinked InRedditWechat Citing Literature Volume47, Issue1January 2007Pages 127-131 RelatedInformation

AIMS/HYPOTHESIS Vildagliptin is a selective dipeptidyl peptidase IV inhibitor that augments meal-stimulated levels of biologically active glucagon-like peptide-1. Chronic vildagliptin treatment decreases postprandial glucose levels and reduces hemoglobin A1c in type 2 diabetic patients. However, little is known about the mechanism(s) by which vildagliptin promotes reduction in plasma glucose concentration. METHODS Sixteen patients with type 2 diabetes (age, 48+/-3 yr; body mass index, 34.4+/-1.7 kg/m2; hemoglobin A1c, 9.0+/-0.3%) participated in a randomized, double-blind, placebo-controlled trial. On separate days patients received 100 mg vildagliptin or placebo at 1730 h followed 30 min later by a meal tolerance test (MTT) performed with double tracer technique (3-(3)H-glucose iv and 1-(14)C-glucose orally). RESULTS After vildagliptin, suppression of endogenous glucose production (EGP) during 6-h MTT was greater than with placebo (1.02+/-0.06 vs. 0.74+/-0.06 mg.kg-1.min-1; P=0.004), and insulin secretion rate increased by 21% (P=0.003) despite significant reduction in mean plasma glucose (213+/-4 vs. 230+/-4 mg/dl; P=0.006). Consequently, insulin secretion rate (area under the curve) divided by plasma glucose (area under the curve) increased by 29% (P=0.01). Suppression of plasma glucagon during MTT was 5-fold greater with vildagliptin (P<0.02). The decline in EGP was positively correlated (r=0.55; P<0.03) with the decrease in fasting plasma glucose (change=-14 mg/dl). CONCLUSIONS During MTT, vildagliptin augments insulin secretion and inhibits glucagon release, leading to enhanced suppression of EGP. During the postprandial period, a single dose of vildagliptin reduced plasma glucose levels by enhancing suppression of EGP.