Management of hyperglycemia associated with pasireotide (SOM230): healthy volunteer study.
OBJECTIVE
Pasireotide, a multireceptor-targeted somatostatin analogue with efficacy in Cushing's disease and acromegaly, can affect glucose metabolism due to inhibition of insulin secretion and incretin hormone responses. A study was therefore conducted to evaluate different antihyperglycemic drugs in the management of pasireotide-associated hyperglycemia.


METHODS
This was a 1-week, Phase I, open-label study. Healthy male volunteers were randomized to pasireotide 600 μg sc bid alone or co-administered with metformin 500 mg po bid, nateglinide 60 mg po tid, vildagliptin 50mg po bid, or liraglutide 0.6 mg sc qd. An oral glucose tolerance test (OGTT) was performed on days 1 and 7 to evaluate effects on serum insulin, plasma glucose and glucagon levels. Safety/tolerability and pharmacokinetic effects were also evaluated.


RESULTS
Ninety healthy male volunteers were enrolled (n=18 per arm). After 7 days of treatment, plasma glucose AUC post-OGTT increased by 69% with pasireotide alone. The effect was reduced by 13%, 29%, 45% and 72% with co-administration of metformin, nateglinide, vildagliptin and liraglutide, respectively. On day 7, compared with pasireotide alone, the decrease in serum insulin was attenuated with nateglinide, metformin, liraglutide and vildagliptin co-administration (levels were 3%, 6%, 34% and 71% higher, respectively). Minimal changes in plasma glucagon were observed. Adverse events were consistent with the safety profiles of the drugs used.


CONCLUSIONS
Vildagliptin and liraglutide were most effective in minimizing pasireotide-associated hyperglycemia in healthy volunteers.
Early Phase Clinical Unit - Berlin, Parexel International GmbH, Klinikum Westend - Haus 18, Spandauer Damm 130, 14050 Berlin, Germany.
Astrid
A
Breitschaft
Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
Ke
K
Hu
Novartis Pharmaceuticals Corporation, Florham Park, NJ, USA.
Karina
K
Hermosillo Reséndiz
Novartis Pharma AG, Basel, Switzerland.
Christelle
C
Darstein
Early Phase Clinical Unit - Berlin, Parexel International GmbH, Klinikum Westend - Haus 18, Spandauer Damm 130, 14050 Berlin, Germany. Electronic address: georg.golor@parexel.com.
Georg
G
Golor
D000218:Adamantane / Q000031:analogs & derivatives / Q000627:therapeutic use; D000293:Adolescent; D000328:Adult; D001786:Blood Glucose / Q000187:drug effects; D003510:Cyclohexanes / Q000627:therapeutic use; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use; D004359:Drug Therapy, Combination; D005934:Glucagon / Q000097:blood / Q000187:drug effects; D052216:Glucagon-Like Peptide 1 / Q000031:analogs & derivatives / Q000627:therapeutic use; D005951:Glucose Tolerance Test; D064368:Healthy Volunteers; D006801:Humans; D006943:Hyperglycemia / Q000139:chemically induced* / Q000188:drug therapy*; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood; D000069450:Liraglutide; D008297:Male; D020714:Maximum Tolerated Dose; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D000077715:Nateglinide; D009570:Nitriles / Q000627:therapeutic use; D010649:Phenylalanine / Q000031:analogs & derivatives / Q000627:therapeutic use; D011379:Prognosis; D011759:Pyrrolidines / Q000627:therapeutic use; D013004:Somatostatin / Q000009:adverse effects / Q000031:analogs & derivatives*; D000077597:Vildagliptin; D055815:Young Adult
D001786:Blood Glucose; D003510:Cyclohexanes; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D011759:Pyrrolidines; D000077715:Nateglinide; D010649:Phenylalanine; D013004:Somatostatin; D000069450:Liraglutide; D052216:Glucagon-Like Peptide 1; D005934:Glucagon; D008687:Metformin; C517782:pasireotide; D000077597:Vildagliptin; D000218:Adamantane
Glucose; Hyperglycemia; Pasireotide; Somatostatin analogue