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

Aila Rissanen, C. P. Howard, J. Botha, T. Thuren, Joseph Proietto, Geoffrey Nicholson, Peter Colman, Ronnie Aronson, Ronald Goldenberg, Hasnain Khandwala, Richard Dumas, Jean Pierre Hallé, Aila Rissanen, Sirkka Keinanen-Kiukaanniemi, Merja Laine, Helmut Anderten, Uwe Boeckmann, Julia Chevts, Winfried Keuthage, Klaus Funke & 34 others Andrei Khariouzov, Joerg Luedemann, Stephan Martin, Thorsten Rau, Reinhold Schneider, Gerhard Steinmaier, Ulrike Venschott-Jordan, Ingo Zeissig, Sunil Jain, Aarti Dharskar, Sanjay Reddy, Sathyanarayana Srikanta, Kav Subrahmanyam, V. Mohan, Rajendran K. Nair, Shailaja Kale, Francesco Dotta, Antonio Pontiroli, Giorgio Pagani, Andrea Giaccari, Esio Ronchi, Piermarco Piatti, Giorgio Luciano Viviani, Robert J. Anderson, Charles M. Arena, Robert Burton, James Lane, Andrew Lewin, Michael Lillestol, Jerry R. Mitchell, Bryce Palchick, Julio Rosenstock, Bret Wittmer, Robert Lipetz

Research output: Contribution to journalArticle

73 Citations (Scopus)

Abstract

Aims: 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/m2/mmol/l; p=0.0525} and in the IGT group (PE 3.92 pmol/min/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.

Original languageEnglish
Pages (from-to)1088-1096
Number of pages9
JournalDiabetes, Obesity and Metabolism
Volume14
Issue number12
DOIs
StatePublished - Dec 2012
Externally publishedYes

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Glucose Intolerance
Interleukin-1
Type 2 Diabetes Mellitus
Randomized Controlled Trials
Placebos
Insulin
Antibodies
Metformin
Glucose
canakinumab
Hyperglycemia
Area Under Curve
Fasting

All Science Journal Classification (ASJC) codes

  • Internal Medicine
  • Endocrinology
  • Endocrinology, Diabetes and Metabolism
  • Medicine(all)

Cite this

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. / Rissanen, Aila; Howard, C. P.; Botha, J.; Thuren, T.; Proietto, Joseph; Nicholson, Geoffrey; Colman, Peter; Aronson, Ronnie; Goldenberg, Ronald; Khandwala, Hasnain; Dumas, Richard; Hallé, Jean Pierre; Rissanen, Aila; Keinanen-Kiukaanniemi, Sirkka; Laine, Merja; Anderten, Helmut; Boeckmann, Uwe; Chevts, Julia; Keuthage, Winfried; Funke, Klaus; Khariouzov, Andrei; Luedemann, Joerg; Martin, Stephan; Rau, Thorsten; Schneider, Reinhold; Steinmaier, Gerhard; Venschott-Jordan, Ulrike; Zeissig, Ingo; Jain, Sunil; Dharskar, Aarti; Reddy, Sanjay; Srikanta, Sathyanarayana; Subrahmanyam, Kav; Mohan, V.; Nair, Rajendran K.; Kale, Shailaja; Dotta, Francesco; Pontiroli, Antonio; Pagani, Giorgio; Giaccari, Andrea; Ronchi, Esio; Piatti, Piermarco; Viviani, Giorgio Luciano; Anderson, Robert J.; Arena, Charles M.; Burton, Robert; Lane, James; Lewin, Andrew; Lillestol, Michael; Mitchell, Jerry R.; Palchick, Bryce; Rosenstock, Julio; Wittmer, Bret; Lipetz, Robert.

In: Diabetes, Obesity and Metabolism, Vol. 14, No. 12, 12.2012, p. 1088-1096.

Research output: Contribution to journalArticle

Rissanen, A, Howard, CP, Botha, J, Thuren, T, Proietto, J, Nicholson, G, Colman, P, Aronson, R, Goldenberg, R, Khandwala, H, Dumas, R, Hallé, JP, Rissanen, A, Keinanen-Kiukaanniemi, S, Laine, M, Anderten, H, Boeckmann, U, Chevts, J, Keuthage, W, Funke, K, Khariouzov, A, Luedemann, J, Martin, S, Rau, T, Schneider, R, Steinmaier, G, Venschott-Jordan, U, Zeissig, I, Jain, S, Dharskar, A, Reddy, S, Srikanta, S, Subrahmanyam, K, Mohan, V, Nair, RK, Kale, S, Dotta, F, Pontiroli, A, Pagani, G, Giaccari, A, Ronchi, E, Piatti, P, Viviani, GL, Anderson, RJ, Arena, CM, Burton, R, Lane, J, Lewin, A, Lillestol, M, Mitchell, JR, Palchick, B, Rosenstock, J, Wittmer, B & Lipetz, R 2012, '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', Diabetes, Obesity and Metabolism, vol. 14, no. 12, pp. 1088-1096. https://doi.org/10.1111/j.1463-1326.2012.01637.x
Rissanen, Aila ; Howard, C. P. ; Botha, J. ; Thuren, T. ; Proietto, Joseph ; Nicholson, Geoffrey ; Colman, Peter ; Aronson, Ronnie ; Goldenberg, Ronald ; Khandwala, Hasnain ; Dumas, Richard ; Hallé, Jean Pierre ; Rissanen, Aila ; Keinanen-Kiukaanniemi, Sirkka ; Laine, Merja ; Anderten, Helmut ; Boeckmann, Uwe ; Chevts, Julia ; Keuthage, Winfried ; Funke, Klaus ; Khariouzov, Andrei ; Luedemann, Joerg ; Martin, Stephan ; Rau, Thorsten ; Schneider, Reinhold ; Steinmaier, Gerhard ; Venschott-Jordan, Ulrike ; Zeissig, Ingo ; Jain, Sunil ; Dharskar, Aarti ; Reddy, Sanjay ; Srikanta, Sathyanarayana ; Subrahmanyam, Kav ; Mohan, V. ; Nair, Rajendran K. ; Kale, Shailaja ; Dotta, Francesco ; Pontiroli, Antonio ; Pagani, Giorgio ; Giaccari, Andrea ; Ronchi, Esio ; Piatti, Piermarco ; Viviani, Giorgio Luciano ; Anderson, Robert J. ; Arena, Charles M. ; Burton, Robert ; Lane, James ; Lewin, Andrew ; Lillestol, Michael ; Mitchell, Jerry R. ; Palchick, Bryce ; Rosenstock, Julio ; Wittmer, Bret ; Lipetz, Robert. / 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. In: Diabetes, Obesity and Metabolism. 2012 ; Vol. 14, No. 12. pp. 1088-1096.
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abstract = "Aims: 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/m2/mmol/l; p=0.0525} and in the IGT group (PE 3.92 pmol/min/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.",
author = "Aila Rissanen and Howard, {C. P.} and J. Botha and T. Thuren and Joseph Proietto and Geoffrey Nicholson and Peter Colman and Ronnie Aronson and Ronald Goldenberg and Hasnain Khandwala and Richard Dumas and Hall{\'e}, {Jean Pierre} and Aila Rissanen and Sirkka Keinanen-Kiukaanniemi and Merja Laine and Helmut Anderten and Uwe Boeckmann and Julia Chevts and Winfried Keuthage and Klaus Funke and Andrei Khariouzov and Joerg Luedemann and Stephan Martin and Thorsten Rau and Reinhold Schneider and Gerhard Steinmaier and Ulrike Venschott-Jordan and Ingo Zeissig and Sunil Jain and Aarti Dharskar and Sanjay Reddy and Sathyanarayana Srikanta and Kav Subrahmanyam and V. Mohan and Nair, {Rajendran K.} and Shailaja Kale and Francesco Dotta and Antonio Pontiroli and Giorgio Pagani and Andrea Giaccari and Esio Ronchi and Piermarco Piatti and Viviani, {Giorgio Luciano} and Anderson, {Robert J.} and Arena, {Charles M.} and Robert Burton and James Lane and Andrew Lewin and Michael Lillestol and Mitchell, {Jerry R.} and Bryce Palchick and Julio Rosenstock and Bret Wittmer and Robert Lipetz",
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TY - JOUR

T1 - Effect of anti-IL-1β antibody (canakinumab) on insulin secretion rates in impaired glucose tolerance or type 2 diabetes

T2 - Results of a randomized, placebo-controlled trial

AU - Rissanen, Aila

AU - Howard, C. P.

AU - Botha, J.

AU - Thuren, T.

AU - Proietto, Joseph

AU - Nicholson, Geoffrey

AU - Colman, Peter

AU - Aronson, Ronnie

AU - Goldenberg, Ronald

AU - Khandwala, Hasnain

AU - Dumas, Richard

AU - Hallé, Jean Pierre

AU - Rissanen, Aila

AU - Keinanen-Kiukaanniemi, Sirkka

AU - Laine, Merja

AU - Anderten, Helmut

AU - Boeckmann, Uwe

AU - Chevts, Julia

AU - Keuthage, Winfried

AU - Funke, Klaus

AU - Khariouzov, Andrei

AU - Luedemann, Joerg

AU - Martin, Stephan

AU - Rau, Thorsten

AU - Schneider, Reinhold

AU - Steinmaier, Gerhard

AU - Venschott-Jordan, Ulrike

AU - Zeissig, Ingo

AU - Jain, Sunil

AU - Dharskar, Aarti

AU - Reddy, Sanjay

AU - Srikanta, Sathyanarayana

AU - Subrahmanyam, Kav

AU - Mohan, V.

AU - Nair, Rajendran K.

AU - Kale, Shailaja

AU - Dotta, Francesco

AU - Pontiroli, Antonio

AU - Pagani, Giorgio

AU - Giaccari, Andrea

AU - Ronchi, Esio

AU - Piatti, Piermarco

AU - Viviani, Giorgio Luciano

AU - Anderson, Robert J.

AU - Arena, Charles M.

AU - Burton, Robert

AU - Lane, James

AU - Lewin, Andrew

AU - Lillestol, Michael

AU - Mitchell, Jerry R.

AU - Palchick, Bryce

AU - Rosenstock, Julio

AU - Wittmer, Bret

AU - Lipetz, Robert

PY - 2012/12

Y1 - 2012/12

N2 - Aims: 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/m2/mmol/l; p=0.0525} and in the IGT group (PE 3.92 pmol/min/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.

AB - Aims: 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/m2/mmol/l; p=0.0525} and in the IGT group (PE 3.92 pmol/min/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.

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