Retrospective Cohort Study
Copyright ©The Author(s) 2017. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Diabetes. Mar 15, 2017; 8(3): 104-111
Published online Mar 15, 2017. doi: 10.4239/wjd.v8.i3.104
Statin, testosterone and phosphodiesterase 5-inhibitor treatments and age related mortality in diabetes
Geoffrey Hackett, Peter W Jones, Richard C Strange, Sudarshan Ramachandran
Geoffrey Hackett, Department of Urology, University of Bed-fordshire, Bedfordshire, Luton LU1 3JU, United Kingdom
Geoffrey Hackett, Department of Urology, Heart of England NHS Foundation Trust, West Midlands B75 7RR, United Kingdom
Peter W Jones, Richard C Strange, Metabolic Research Group, Institute of Science and Technology in Medicine, Keele University, Keele ST5 5BG, United Kingdom
Sudarshan Ramachandran, Department of Clinical Biochemistry, Heart of England NHS Foundation Trust, West Midlands B75 7RR, United Kingdom
Sudarshan Ramachandran, Department of Clinical Biochemistry, University Hospitals of North Midlands/Faculty of Health Sciences, Staffordshire University, Stoke-on-Trent ST4 2DE, United Kingdom
Author contributions: The original study was designed by Hackett G; Strange RC and Ramachandran S have had an interest in the work of Gompertz B and conceived the idea of investigating age related mortality patterns in different cohorts and studying how interventions alter age related mortality; all authors contributed to the data analysis this work being supervised by Jones PW as well as drafting, revising and approving the final version of the manuscript.
Supported by Bayer plc to University of Bedfordshire (ref: SOP ID: BSP-SOP-040); Bayer plc played no part in the design, conduct of the study, data collection, statistical analyses or preparation of the manuscript.
Institutional review board statement: The study was reviewed and approved by the following bodies: National Research Ethics Service (West Midlands Ethics Service) 08/H1208/30; National Institute for Health Research (Birmingham and the Black Country Comprehensive Local Research Network), RM and G reference Number 1268; Warwickshire Primary Care Trust (West Midlands (South) Comprehensive Local Research Network), reference WAR230909; Institute of Diabetes for Older People, Beds and Herts Postgraduate Medical School, University of Bedfordshire (ref: SOP ID: BSP-SOP-040); Bayer plc (ref: SOP ID: BSP-SOP-040): funding organisation; Institute for Science and Technology in Medicine, Keele University Medical School: approval for publication (Professor N Forsyth, Director of the Institute).
Informed consent statement: All participants in the intervention study (BLAST) provided informed written consent prior to study enrolment. The long term follow-up of the screened individuals receiving standard care was approved as an audit by Primary Care Trusts.
Conflict-of-interest statement: No potential conflicts of interest relevant to this article were reported.
Data sharing statement: Technical appendix, statistical code, and dataset are available from the corresponding author at (sud.ramachandran@heartofengland.nhs.uk). Participants gave informed consent for anonymous data to be shared with health authorities and published in scientific journals.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Sudarshan Ramachandran, PhD, FRC Path, Professor, Department of Clinical Biochemistry, Heart of England NHS Foundation Trust, Rectory Road, Sutton Coldfield, West Midlands B75 7RR, United Kingdom. sud.ramachandran@heartofengland.nhs.uk
Telephone: +44-121-4247246 Fax: +44-121-3111800
Received: October 27, 2016
Peer-review started: October 31, 2016
First decision: December 1, 2016
Revised: December 14, 2016
Accepted: January 2, 2017
Article in press: January 3, 2017
Published online: March 15, 2017
Processing time: 133 Days and 0.2 Hours
Abstract
AIM

To determine how statins, testosterone (T) replacement therapy (TRT) and phosphodiesterase 5-inhibitors (PDE5I) influence age related mortality in diabetic men.

METHODS

We studied 857 diabetic men screened for the BLAST study, stratifying them (mean follow-up = 3.8 years) into: (1) Normal T levels/untreated (total T > 12 nmol/L and free T > 0.25 nmol/L), Low T/untreated and Low T/treated; (2) PDE5I/untreated and PDE5I/treated; and (3) statin/untreated and statin/treated groups. The relationship between age and mortality, alone and with T/TRT, statin and PDE5I treatment was studied using logistic regression. Mortality probability and 95%CI were calculated from the above models for each individual.

RESULTS

Age was associated with mortality (logistic regression, OR = 1.10, 95%CI: 1.08-1.13, P < 0.001). With all factors included, age (OR = 1.08, 95%CI: 1.06-1.11, P < 0.001), Low T/treated (OR = 0.38, 95%CI: 0.15-0.92, P = 0.033), PDE5I/treated (OR = 0.17, 95%CI: 0.053-0.56, P = 0.004) and statin/treated (OR = 0.59, 95%CI: 0.36-0.97, P = 0.038) were associated with lower mortality. Age related mortality was as described by Gompertz, r2 = 0.881 when Ln (mortality) was plotted against age. The probability of mortality and 95%CI (from logistic regression) of individuals, treated/untreated with the drugs, alone and in combination was plotted against age. Overlap of 95%CI lines was evident with statins and TRT. No overlap was evident with PDE5I alone and with statins and TRT, this suggesting a change in the relationship between age and mortality.

CONCLUSION

We show that statins, PDE5I and TRT reduce mortality in diabetes. PDE5I, alone and with the other treatments significantly alter age related mortality in diabetic men.

Keywords: Type 2 diabetes; Mortality; Gompertz-Makeham equation; Phosphodiesterase 5 inhibitors; Male hypogonadism; Statins; Testosterone replacement therapy

Core tip: We have described a study of men with type 2 diabetes showing that mortality rates are in accordance with the pattern described nearly 200 years ago by Benjamin Gompertz. The data show that statin, phosphodiesterase 5 inhibitors (PDE5I) and testosterone replacement in hypogonadal men reduce all-cause mortality. PDE5I, alone and in combination with the other 2 agents alters the association between age and mortality, thus improving prognosis. The graphical illustrations adopted in this paper communicate the impact of medical intervention very effectively to patients and this could potentially improve compliance leading to significant clinical benefit.