Effect of anti-IL-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes: results of a randomized, placebo-controlled trial.
OBJECTIVE
Evaluate anti-interleukin-1β (IL-1β) antibody, canakinumab, in patients with type 2 diabetes and impaired glucose tolerance (IGT) in whom hyperglycaemia may trigger IL-1β-associated inflammation leading to suppressed insulin secretion and β-cell dysfunction.


METHODS
This 4-week, parallel-group study randomized 190 patients with type 2 diabetes 2 : 1, canakinumab versus placebo, into the following treatment arms: metformin monotherapy, metformin + sulfonylurea, metformin + sulfonylurea + thiazolidinedione or insulin ± metformin. IGT population (n = 54) was randomized 1 : 1, canakinumab versus placebo. Primary efficacy assessment was change from baseline in insulin secretion rate (ISR) relative to glucose 0-2 h.


RESULTS
Mean changes from baseline to week 4 in ISR relative to glucose at 0-2 h or other time points were not statistically significant for canakinumab versus placebo across groups. ISR (relative to glucose) at 0-0.5 h (first-phase insulin secretion) numerically favoured canakinumab versus placebo in insulin-treated patients {difference in mean change from baseline [point estimate (PE)] 3.81 pmol/min/m(2)/mmol/l; p = 0.0525} and in the IGT group (PE 3.92 pmol/min/m(2)/mmol/l; p = 0.1729). Mean change from baseline in fasting plasma glucose favoured canakinumab in the type 2 diabetes/metformin group and the IGT group; however, differences were not statistically significant. Mean change from baseline in peak insulin level and insulin AUC 0-4 h were statistically significantly higher in the canakinumab group in IGT patients. Canakinumab was well tolerated and consistent with known safety experience.


CONCLUSIONS
The trend towards improving ISR relative to glucose 0-0.5 h in patients treated with insulin supports the hypothesis that insulin secretion can be improved by blocking IL-1β.
Obesity Research Unit, Helsinki University Central Hospital, Helsinki, Finland.
A
A
Rissanen
C P
CP
Howard
J
J
Botha
T
T
Thuren
D000293:Adolescent; D000328:Adult; D000368:Aged; D000911:Antibodies, Monoclonal / Q000494:pharmacology / Q000627:therapeutic use*; D061067:Antibodies, Monoclonal, Humanized; D001786:Blood Glucose / Q000378:metabolism*; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D004311:Double-Blind Method; D004334:Drug Administration Schedule; D005260:Female; D018149:Glucose Intolerance / Q000188:drug therapy* / Q000276:immunology / Q000378:metabolism; D006801:Humans; D006943:Hyperglycemia / Q000188:drug therapy; D007004:Hypoglycemic Agents / Q000494:pharmacology / Q000627:therapeutic use*; D007328:Insulin / Q000378:metabolism*; D000078790:Insulin Secretion; D053583:Interleukin-1beta / Q000037:antagonists & inhibitors*; D008297:Male; D008687:Metformin / Q000627:therapeutic use; D008875:Middle Aged; D013453:Sulfonylurea Compounds / Q000627:therapeutic use; D045162:Thiazolidinediones / Q000627:therapeutic use; D016896:Treatment Outcome
D000911:Antibodies, Monoclonal; D061067:Antibodies, Monoclonal, Humanized; D001786:Blood Glucose; D007004:Hypoglycemic Agents; D007328:Insulin; D053583:Interleukin-1beta; D013453:Sulfonylurea Compounds; D045162:Thiazolidinediones; C541220:canakinumab; D008687:Metformin; C089946:2,4-thiazolidinedione