Effect of high-dose pitavastatin on glucose homeostasis in patients at elevated risk of new-onset diabetes: insights from the CAPITAIN and PREVAIL-US studies

Abstract

Aims:

Statin treatment may impair glucose homeostasis and increase the risk of new-onset diabetes mellitus, although this may depend on the statin, dose and patient population. We evaluated the effects of pitavastatin 4 mg/day on glucose homeostasis in patients with metabolic syndrome in the CAPITAIN trial. Findings were validated in a subset of patients enrolled in PREVAIL-US.

Methods:

Participants with a well defined metabolic syndrome phenotype were recruited to CAPITAIN to reduce the influence of confounding factors. Validation and comparison datasets were selected comprising phenotypically similar subsets of individuals enrolled in PREVAIL-US and treated with pitavastatin or pravastatin, respectively. Mean change from baseline in parameters of glucose homeostasis (fasting plasma glucose [FPG], glycated hemoglobin [HbA_1c], insulin, quantitative insulin-sensitivity check index [QUICKI] and homeostasis model of assessment–insulin resistance [HOMA-IR]) and plasma lipid profile were assessed at 6 months (CAPITAIN) and 3 months (PREVAIL-US) after initiating treatment.

Results:

In CAPITAIN (n = 12), no significant differences from baseline in HbA1c, insulin, HOMA-IR and QUICKI were observed at day 180 in patients treated with pitavastatin. A small (4%) increase in FPG from baseline to day 180 (P < 0.05), was observed. In the validation dataset (n = 9), no significant differences from baseline in glycemic parameters were observed at day 84 (all comparisons P > 0.05). Similar results were observed for pravastatin in the comparison dataset (n = 14).

Conclusions:

Other than a small change in FPG in the CAPITAIN study, neutral effects of pitavastatin on glucose homeostasis were observed in two cohorts of patients with metabolic syndrome, independent of its efficacy in reducing levels of atherogenic lipoproteins. The small number of patients and relatively short follow-up period represent limitations of the study. Nevertheless, these data suggest that statin-induced diabetogenesis may not represent a class effect.

Keywords::

• Diabetogenicity
• Dyslipidemia
• Glucose homeostasis
• Lipid profile
• Metabolic syndrome
• Statin

Transparency

Declaration of funding

The CAPITAIN study was supported by a research grant from Kowa Research Europe to Dr M.J. Chapman. The PREVAIL-US study was funded by Kowa Pharmaceuticals America Inc. and Eli Lilly & Company.

Author contributions: M.J.C., P.G. and N.H. conceived the CAPITAIN study and participated in its design and in drafting the manuscript. C.A.S. identified and contributed data from the PREVAIL-US study subset of metabolic syndrome subjects and contributed to drafting the manuscript. P.R. and A.O. performed biological analyses and contributed to the manuscript draft. P.G., P.R. and A.O. performed statistical analyses of the datasets. All authors participated in discussion of the interpretation of the experimental data and read and approved the final manuscript.

Declaration of financial/other relationships

M.J.C. has received research funding from CSL Behring, Kowa Research Europe, Merck, Pfizer and Randox, and has served on Advisory Boards for Danone, Kowa Research Europe, Merck, Pfizer and Sanofi-Regeneron. N.H. is an employee of Kowa Research Europe. C.A.S. is an employee of Kowa Pharmaceuticals America Inc. P.G., P.R. and A.O. have disclosed that they have no significant relationships with or financial interests in any commercial companies related to this study or article.

CMRO peer reviewers may have received honoraria for their review work. The peer reviewers on this manuscript have disclosed that they have no relevant financial relationships.

Acknowledgments

We are indebted to INSERM, the Nouvelle Société Française d’Athérosclérose (NSFA), and the Association for Research on Lipoproteins and Atherogenesis (ARLA) for support of these studies. We are indebted to Dr John Lamont (Randox Laboratories) for the kind gift of biochip arrays, to Mr Michi Suzuki for critical and logistical support in clinical studies, and to Dr Philippe Betting and Colleagues at SGS Aster Paris for patient recruitment and follow-up. The authors take full responsibility for the content of this paper. Dr Nick Leach (Oxford PharmaGenesis) provided editorial support in developing the manuscript, funded by Kowa Research Europe.

Previous presentation: Parts of this analysis have been presented in poster format at the 81st European Atherosclerosis Society (EAS) Congress, 2–5 June 2013, in Lyon, France, and also at the 7th World Congress on Prevention of Diabetes and its Complications, 11–14 November 2012, in Madrid, Spain.