Condition category
Circulatory System
Date applied
16/07/2007
Date assigned
27/07/2007
Last edited
12/05/2011
Prospective/Retrospective
Retrospectively registered
Overall trial status
Completed
Recruitment status
No longer recruiting

Plain English Summary

Not provided at time of registration

Trial website

Contact information

Type

Scientific

Primary contact

Dr Krishnan Swaminathan

ORCID ID

Contact details

Department of Clinical Pharmacology
Level 7
Ninewells Hospital
Dundee
DD1 9SY
United Kingdom
+44 1382 632180
krishnan.swaminathan@nhs.net

Additional identifiers

EudraCT number

ClinicalTrials.gov number

Protocol/serial number

SAM 001

Study information

Scientific title

Acronym

Study hypothesis

Patients with diabetes are at particularly high risk of cardiovascular disease. Infact, macrovascular disease accounts for 70 % of the mortality in type 2 diabetes, making heart attacks and strokes two to four times more frequent in these patients compared to controls. The combination of diabetes and hypertension is a particularly strong cardiovascular risk factor. Vascular endothelial dysfunction is a recognised risk factor for cardiovascular mortality. Blocking aldosterone with spironolactone in patients with cardiac failure can reverse endothelial dysfunction in this patient group, as well as improving the prognostic markers of PIIINP, BNP and heart rate variability. Additionally, the RALES (Randomised Aldactone Evaluation Study) and EPHESUS (Eplerenone Postacute myocardial infarction Heart failure Efficacy and Survival Study) studies have shown a dramatic reduction in total mortality (approximately 30%) with aldosterone blockade in patients with heart failure already taking the recognised optimum treatment for this condition. This lends weight to the concept that reducing endothelial dysfunction by spironolactone may be associated with reduction in real cardiovascular events.

The question then arose whether similar benefits might be seen in other diseases. It was therefore somewhat surprising that in a normotensive population of patients with type 2 diabetes, spironolactone actually worsened the key prognostic marker of endothelial function while also worsening glycaemic control. The situation might however be different in diabetics with poorly controlled hypertension where a spironolactone induced fall in BP might instead lead to an improvement in endothelial and autonomic function. We therefore studied whether, in patients with type 2 diabetes mellitus and poorly controlled hypertension, taking low-dose spironolactone in addition to their normal cardiovascular medication, would improve the important prognostic marker of endothelial function, as logic suggests that this should be of benefit. In addition we wish to investigate whether spironolactone treatment also brings about an improvement in the other prognostic markers of PIIINP, BNP and heart rate variability. We also wanted to see if the spironolactone induced worsening of glycaemic control that we saw in a previous study in normotensive diabetics was reproducible.

Ethics approval

The Tayside Committee for Medical Ethics, Scotland, approved on 28/09/2004 (ref: 236/03)

Study design

Randomized, placebo-controlled, double-blind, cross-over design.

Primary study design

Interventional

Secondary study design

Randomised controlled trial

Trial setting

Not specified

Trial type

Not Specified

Patient information sheet

Condition

Type 2 diabetes mellitus and hypertension

Intervention

In this cross-over study, each participant was treated with two different drugs and a placebo, one at a time, in addition to his or her standard medication. Each drug / placebo treatment lasted for 4 weeks, and there was a 2-week washout period between each treatment (during the washout period participants took their standard medication only). Therefore, the entire duration of the intervention was 16 weeks. Details of the intervention treatments are as follows:
1. Spironolactone, 25 mg orally per day for 1 week, increased to 50 mg per day for the next 3 weeks if potassium levels were within normal limits (total duration of treatment 4 weeks)
2. Amlodipine, 5 mg orally per day for 4 weeks
3. Placebo for 4 weeks

Intervention type

Drug

Phase

Not Specified

Drug names

Spironolactone, Amlodipine

Primary outcome measures

Improvement in endothelial function, assessed 24 months after the start of the trial.

Secondary outcome measures

The following were assessed 24 months after the start of the trial:
1. Improvement in the other prognostic markers of PIIINP and B-type Natriuretic Peptide (BNP)
2. Improvement in heart rate variability

Overall trial start date

01/01/2005

Overall trial end date

31/12/2006

Reason abandoned

Eligibility

Participant inclusion criteria

Patients with type 2 diabetes mellitus and hypertension who were on standard treatment were recruited. All patients were on either Angiotensin Converting Enzyme (ACE) inhibitors or angiotensin receptor blockers.

Participant type

Patient

Age group

Not Specified

Gender

Both

Target number of participants

50

Participant exclusion criteria

1. Blood pressure <140 mm Hg systolic and 80 mm Hg diastolic
2. Recent admission to hospital within last 4 weeks
3. History of alcohol abuse
4. Liver or renal impairment
5. Heart failure
6. On potassium sparing diuretics, insulin or warfarin (procedural risks)

Recruitment start date

01/01/2005

Recruitment end date

31/12/2006

Locations

Countries of recruitment

United Kingdom

Trial participating centre

Department of Clinical Pharmacology
Dundee
DD1 9SY
United Kingdom

Sponsor information

Organisation

Tenovus Scotland (UK)

Sponsor details

234 St. Vincent Street
Glasgow
G2 5RJ
United Kingdom
+44 (0)1292 311276
gen.sec@talk21.com

Sponsor type

Charity

Website

http://www.tenovus-scotland.org.uk/TS_homepage.html

Funders

Funder type

Charity

Funder name

Tenovus Scotland (ref: T03/21) (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Funder name

Northwood Trust (UK)

Alternative name(s)

Funding Body Type

Funding Body Subtype

Location

Results and Publications

Publication and dissemination plan

Not provided at time of registration

Intention to publish date

Participant level data

Not provided at time of registration

Results - basic reporting

Publication summary

2008 results in http://www.ncbi.nlm.nih.gov/pubmed/18347776

Publication citations

  1. Results

    Swaminathan K, Davies J, George J, Rajendra NS, Morris AD, Struthers AD, Spironolactone for poorly controlled hypertension in type 2 diabetes: conflicting effects on blood pressure, endothelial function, glycaemic control and hormonal profiles., Diabetologia, 2008, 51, 5, 762-768, doi: 10.1007/s00125-008-0972-5.

Additional files

Editorial Notes