ORIGINAL ARTICLE
original article
Diabetes, Obesity and Metabolism 17: 560–565, 2015. © 2015 John Wiley & Sons Ltd
Efficacy, safety and tolerability of aleglitazar in patients with type 2 diabetes: pooled findings from three randomized phase III trials R. R. Henry1 , J. B. Buse2 , H. Wu3 , L. Durrwell4 , R. Mingrino4 , K. Jaekel4 , B. El Azzouzi4 , M. Andjelkovic4 & M. Herz4 1 Center for Metabolic Research, VA San Diego Healthcare System, University of California, San Diego, CA, USA 2 Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA 3 Roche (China) Holding Ltd, Beijing, China 4 F. Hoffmann-La Roche Ltd, Basel, Switzerland
Aims: To evaluate the potential efficacy, safety and tolerability of aleglitazar as monotherapy or add-on therapy to metformin or to a sulphonylurea (either alone or in combination with metformin). Methods: We conducted a pooled analysis of data from three randomized phase III clinical trials of aleglitazar in patients with type 2 diabetes (n = 591). The three studies focused on: (i) aleglitazar alone; (ii) aleglitazar and metformin; and (iii) aleglitazar and sulphonylurea with or without metformin. Patients were randomized to 26 weeks’ treatment with aleglitazar 150 μg/day or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) concentration from baseline to week 26. Secondary endpoints included changes in lipids, fasting plasma glucose and homeostatic model assessment of insulin resistance (HOMA-IR) at week 26. Results: Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. Aleglitazar treatment was associated with more beneficial changes in lipid profiles and HOMA-IR values than was placebo. Aleglitazar was generally well tolerated, with no reports of congestive heart failure. The incidence of peripheral oedema was similar in both groups. Change in body weight was +1.37 kg with aleglitazar and −0.53 kg with placebo. Hypoglycaemia was more frequently reported with aleglitazar (7.8%) than with placebo (1.7%), a result probably driven by the type of background medication. Conclusions: Development of aleglitazar was halted because of a lack of cardiovascular efficacy and peroxisome proliferator-activated receptor-related side effects in patients with type 2 diabetes post-acute coronary syndrome; however, in the present studies, aleglitazar was well tolerated and effective in improving HbA1c, insulin resistance and lipid variables. Keywords: glycaemic control, lipid-lowering therapy, metformin, PPAR-gamma agonist, sulphonylureas, type 2 diabetes Date submitted 18 November 2014; date of first decision 1 January 2015; date of final acceptance 22 February 2015
Introduction It is well established that chronic hyperglycaemia is responsible for many diabetes-related complications and that long-term glycaemic control can reduce the risk of microvascular complications; however, whether or not reduction of the cardiovascular risk associated with type 2 diabetes is achievable with antihyperglycaemic agents is less conclusive [1–3]. The dual peroxisome proliferator-activated receptor (PPAR) agonist alegitazar exerts antihyperglycaemic and lipid profile-modifying effects via balanced activation of PPAR-𝛼 and -𝛾 [4], leading to insulin-sensitizing and glucose-lowering actions, and favourable effects on lipid profiles and biomarkers of cardiovascular risk [5]. With a mechanism of action complementary to that of metformin and sulphonylurea, and a low risk of hypoglycaemia, co-administration of an agent such Correspondence to : Robert R. Henry, MD, Center for Metabolic Research, VA San Diego Healthcare System, University of California, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. E-mail: [email protected]
as aleglitazar was believed to be a rational step for improving glycaemic control while addressing other factors associated with cardiovascular risk. The development plan for the drug hinged on the demonstration of reduced cardiovascular endpoints in a high-risk population. After a regular safety review of the AleCardio phase III trial, which examined the addition of aleglitazar to standard-of-care medication to reduce cardiovascular morbidity and mortality in patients with type 2 diabetes and a recent acute coronary syndrome event, the development programme for aleglitazar was halted because of lack of cardiovascular efficacy and PPAR-related adverse events (AEs) [6]. Three multicentre phase III trials, together comprising the AleGlucose programme, aimed to evaluate the potential role of aleglitazar as monotherapy, or add-on therapy to metformin or to sulphonylurea (alone/in combination with metformin). The results are relevant despite discontinuation of the aleglitazar programme, as they describe the potential benefits and harms of a novel class of antihyperglycaemic agent, the dual PPAR-𝛼/-𝛾 agonist.
original article
DIABETES, OBESITY AND METABOLISM
Materials and Methods Study Design The present pooled analysis of data from three multicentre phase III trials evaluated the effect of aleglitazar on glycaemic control, lipid profile and other markers of insulin sensitivity and cardiovascular risk, as well as safety and tolerability, in patients with type 2 diabetes. Study 1 (NCT01691755) assessed aleglitazar versus placebo in patients who were drug-naïve to antihyperglycaemic therapy. Study 2 (NCT01691846) evaluated aleglitazar plus metformin versus placebo plus metformin in patients inadequately controlled with metformin alone. Study 3 (NCT01691989) assessed aleglitazar plus sulphonylurea (or plus sulphonylurea in combination with metformin) versus placebo plus sulphonylurea (or plus sulphonylurea combined with metformin) in patients inadequately controlled with sulphonylurea monotherapy or with sulphonylurea plus metformin combination therapy. For study locations, see Appendix S1. The studies were conducted in full conformance with the International Conference on Harmonization E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. Written informed consent was obtained from each patient before they participated in the study. Documented approval of the protocol was obtained from an independent ethics committee/independent review board before starting the study. Each study consisted of a screening visit, a single-blind 2-week run-in period with a pre-randomization visit, a 26-week double-blind treatment period (five visits), and a follow-up visit (study completion visit). A diet and exercise plan to control body weight was discussed and implemented at screening, based on the recommendation of the investigator. Patients who fulfilled all of the inclusion criteria and none of the exclusion criteria (Appendix S1) were randomized using an interactive voice/web response system in a 1 : 1 ratio to 150 μg aleglitazar or matching placebo taken orally once daily for 26 weeks. In Studies 2 and 3, patients continued on their existing dose and regimen of metformin and/or sulphonylurea therapy throughout the study (metformin: ≥1500 mg/day or individual maximally tolerated dose, but not more than the maximum dose specified in the label; sulphonylurea: at least half the maximum country-specific labelled dose or individual maximally tolerated dose). Metformin and/or sulphonylurea dose could be reduced in case of hypoglycaemia. The dose of 150 μg aleglitazar was based on findings from the phase II SYNCHRONY dose-finding trial [5], which found similar glycaemic effects with this dose compared with 45 mg pioglitazone (consistent with 1-year data from the phase II ALENEPHRO trial [7]), with the most favourable safety profile.
Study Participants Approximately 600 patients (200 per study) were planned for randomization in the three phase III studies. Because of the early termination of the alegitazar programme, the primary
Volume 17 No. 6 June 2015
endpoint was only analysed in 103 of the 591 randomized patients who received at least one dose of medication. The studies enrolled men and women aged ≥18 years old with type 2 diabetes, and with glycated haemoglobin (HbA1c) ≥7.0 and ≤9.5% at screening or within 4 weeks prior to screening and at the pre-randomization visit.
Study Endpoints In each of the three studies, the primary efficacy endpoint was change from baseline in HbA1c concentration at week 26. Secondary efficacy endpoints included change from baseline in HDL cholesterol, triglycerides, LDL cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), fasting plasma glucose (FPG) and homeostatic model assessment of insulin resistance (HOMA-IR), all at week 26. Responder rates, defined as target HbA1c
original article
Diabetes, Obesity and Metabolism 17: 560–565, 2015. © 2015 John Wiley & Sons Ltd
Efficacy, safety and tolerability of aleglitazar in patients with type 2 diabetes: pooled findings from three randomized phase III trials R. R. Henry1 , J. B. Buse2 , H. Wu3 , L. Durrwell4 , R. Mingrino4 , K. Jaekel4 , B. El Azzouzi4 , M. Andjelkovic4 & M. Herz4 1 Center for Metabolic Research, VA San Diego Healthcare System, University of California, San Diego, CA, USA 2 Department of Medicine, University of North Carolina School of Medicine, Chapel Hill, NC, USA 3 Roche (China) Holding Ltd, Beijing, China 4 F. Hoffmann-La Roche Ltd, Basel, Switzerland
Aims: To evaluate the potential efficacy, safety and tolerability of aleglitazar as monotherapy or add-on therapy to metformin or to a sulphonylurea (either alone or in combination with metformin). Methods: We conducted a pooled analysis of data from three randomized phase III clinical trials of aleglitazar in patients with type 2 diabetes (n = 591). The three studies focused on: (i) aleglitazar alone; (ii) aleglitazar and metformin; and (iii) aleglitazar and sulphonylurea with or without metformin. Patients were randomized to 26 weeks’ treatment with aleglitazar 150 μg/day or placebo. The primary endpoint was change in glycated haemoglobin (HbA1c) concentration from baseline to week 26. Secondary endpoints included changes in lipids, fasting plasma glucose and homeostatic model assessment of insulin resistance (HOMA-IR) at week 26. Results: Reductions in HbA1c concentration from baseline to week 26 were statistically significantly greater with aleglitazar than with placebo. Aleglitazar treatment was associated with more beneficial changes in lipid profiles and HOMA-IR values than was placebo. Aleglitazar was generally well tolerated, with no reports of congestive heart failure. The incidence of peripheral oedema was similar in both groups. Change in body weight was +1.37 kg with aleglitazar and −0.53 kg with placebo. Hypoglycaemia was more frequently reported with aleglitazar (7.8%) than with placebo (1.7%), a result probably driven by the type of background medication. Conclusions: Development of aleglitazar was halted because of a lack of cardiovascular efficacy and peroxisome proliferator-activated receptor-related side effects in patients with type 2 diabetes post-acute coronary syndrome; however, in the present studies, aleglitazar was well tolerated and effective in improving HbA1c, insulin resistance and lipid variables. Keywords: glycaemic control, lipid-lowering therapy, metformin, PPAR-gamma agonist, sulphonylureas, type 2 diabetes Date submitted 18 November 2014; date of first decision 1 January 2015; date of final acceptance 22 February 2015
Introduction It is well established that chronic hyperglycaemia is responsible for many diabetes-related complications and that long-term glycaemic control can reduce the risk of microvascular complications; however, whether or not reduction of the cardiovascular risk associated with type 2 diabetes is achievable with antihyperglycaemic agents is less conclusive [1–3]. The dual peroxisome proliferator-activated receptor (PPAR) agonist alegitazar exerts antihyperglycaemic and lipid profile-modifying effects via balanced activation of PPAR-𝛼 and -𝛾 [4], leading to insulin-sensitizing and glucose-lowering actions, and favourable effects on lipid profiles and biomarkers of cardiovascular risk [5]. With a mechanism of action complementary to that of metformin and sulphonylurea, and a low risk of hypoglycaemia, co-administration of an agent such Correspondence to : Robert R. Henry, MD, Center for Metabolic Research, VA San Diego Healthcare System, University of California, 3350 La Jolla Village Drive, San Diego, CA 92161, USA. E-mail: [email protected]
as aleglitazar was believed to be a rational step for improving glycaemic control while addressing other factors associated with cardiovascular risk. The development plan for the drug hinged on the demonstration of reduced cardiovascular endpoints in a high-risk population. After a regular safety review of the AleCardio phase III trial, which examined the addition of aleglitazar to standard-of-care medication to reduce cardiovascular morbidity and mortality in patients with type 2 diabetes and a recent acute coronary syndrome event, the development programme for aleglitazar was halted because of lack of cardiovascular efficacy and PPAR-related adverse events (AEs) [6]. Three multicentre phase III trials, together comprising the AleGlucose programme, aimed to evaluate the potential role of aleglitazar as monotherapy, or add-on therapy to metformin or to sulphonylurea (alone/in combination with metformin). The results are relevant despite discontinuation of the aleglitazar programme, as they describe the potential benefits and harms of a novel class of antihyperglycaemic agent, the dual PPAR-𝛼/-𝛾 agonist.
original article
DIABETES, OBESITY AND METABOLISM
Materials and Methods Study Design The present pooled analysis of data from three multicentre phase III trials evaluated the effect of aleglitazar on glycaemic control, lipid profile and other markers of insulin sensitivity and cardiovascular risk, as well as safety and tolerability, in patients with type 2 diabetes. Study 1 (NCT01691755) assessed aleglitazar versus placebo in patients who were drug-naïve to antihyperglycaemic therapy. Study 2 (NCT01691846) evaluated aleglitazar plus metformin versus placebo plus metformin in patients inadequately controlled with metformin alone. Study 3 (NCT01691989) assessed aleglitazar plus sulphonylurea (or plus sulphonylurea in combination with metformin) versus placebo plus sulphonylurea (or plus sulphonylurea combined with metformin) in patients inadequately controlled with sulphonylurea monotherapy or with sulphonylurea plus metformin combination therapy. For study locations, see Appendix S1. The studies were conducted in full conformance with the International Conference on Harmonization E6 guideline for Good Clinical Practice and the principles of the Declaration of Helsinki, or the laws and regulations of the country in which the research was conducted, whichever afforded the greater protection to the individual. Written informed consent was obtained from each patient before they participated in the study. Documented approval of the protocol was obtained from an independent ethics committee/independent review board before starting the study. Each study consisted of a screening visit, a single-blind 2-week run-in period with a pre-randomization visit, a 26-week double-blind treatment period (five visits), and a follow-up visit (study completion visit). A diet and exercise plan to control body weight was discussed and implemented at screening, based on the recommendation of the investigator. Patients who fulfilled all of the inclusion criteria and none of the exclusion criteria (Appendix S1) were randomized using an interactive voice/web response system in a 1 : 1 ratio to 150 μg aleglitazar or matching placebo taken orally once daily for 26 weeks. In Studies 2 and 3, patients continued on their existing dose and regimen of metformin and/or sulphonylurea therapy throughout the study (metformin: ≥1500 mg/day or individual maximally tolerated dose, but not more than the maximum dose specified in the label; sulphonylurea: at least half the maximum country-specific labelled dose or individual maximally tolerated dose). Metformin and/or sulphonylurea dose could be reduced in case of hypoglycaemia. The dose of 150 μg aleglitazar was based on findings from the phase II SYNCHRONY dose-finding trial [5], which found similar glycaemic effects with this dose compared with 45 mg pioglitazone (consistent with 1-year data from the phase II ALENEPHRO trial [7]), with the most favourable safety profile.
Study Participants Approximately 600 patients (200 per study) were planned for randomization in the three phase III studies. Because of the early termination of the alegitazar programme, the primary
Volume 17 No. 6 June 2015
endpoint was only analysed in 103 of the 591 randomized patients who received at least one dose of medication. The studies enrolled men and women aged ≥18 years old with type 2 diabetes, and with glycated haemoglobin (HbA1c) ≥7.0 and ≤9.5% at screening or within 4 weeks prior to screening and at the pre-randomization visit.
Study Endpoints In each of the three studies, the primary efficacy endpoint was change from baseline in HbA1c concentration at week 26. Secondary efficacy endpoints included change from baseline in HDL cholesterol, triglycerides, LDL cholesterol, apolipoprotein A1 (ApoA1), apolipoprotein B (ApoB), fasting plasma glucose (FPG) and homeostatic model assessment of insulin resistance (HOMA-IR), all at week 26. Responder rates, defined as target HbA1c
