A pill could reduce heart attacks and deaths if given to people with type 2 diabetes, reported three newspapers (3 September, 2007). The newspapers were generally accurate in their reports of a well-conducted trial. The extent to which the findings can be generalised to all individuals with type 2 diabetes is unclear.
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On 3rd September 2007 three newspapers (1-3) reported that giving people with type 2 diabetes Coveryl Plus, a combination of perindopril and indapamide used to reduce blood pressure, reduces their risk of heart attacks and diabetes related deaths.
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The research, published in the Lancet (4), was a large double blind randomised controlled trial involving 11140 participants based in 215 centres in 20 countries. Participants were followed up for an average of 4.3 years. The results showed that overall participants who received perindopril and indapamide combination therapy had a statistically significantly greater reduction in blood pressure than participants who received placebo. Participants who received the combination therapy also experienced a statistically significantly risk reduction in all deaths, cardiovascular deaths, total coronary events and in total renal events compared to participants who received placebo.
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The newspaper reports generally provided an accurate overview of the results of the study. All the newspapers reported that people with type 2 diabetes with normal blood pressure could also benefit. The study findings were based on participants aged over 55 who had either a history of major cardiac disease or at least one other risk factor for cardiovascular disease, and who tolerated and adhered to the drug. As such, the extent to which these findings can be generalised to others with type 2 diabetes is unclear.
Evaluation of the evidence base for the reduction of vascular events in people with type 2 diabetes taking perindopril and indapamide combination therapy
Where does the evidence come from?
The study was conducted by the ADVANCE Collaborative Group which includes 215 Centres in 20 Countries. The project was funded by grants from Servier, who manufacture Coveryl Plus, and the National Health and Medical Research Council of Australia.
What were the authors' objectives?
To assess the effects of perindopril and indapamide combination therapy, used to reduce blood pressure, on serious vascular events in people with type 2 diabetes, irrespective of their initial blood pressure levels.
What was the nature of the evidence?
This was a double blind randomised controlled trial involving 11140 people with type 2 diabetes. To be eligible, participants needed to have been at least 30 years old when diabetes was first diagnosed, and at least 55 years on entry to the study. All participants also needed to have either a history of major cardiac disease or at least one other risk factor for cardiovascular disease. Participants were not excluded based on their blood pressure. Randomisation was stratified by study centre, history of disease, and use of perindopril concomitantly. The mean age for participants was 58 years when first diagnosed, and 66 years on entry into the trial. Nearly a third of participants had a history of major macrovascular disease, and approximately 10% had a history of microvascular disease. Forty-one percent of participants had a systolic blood pressure less that 140mm Hg and a diastolic blood pressure less than 90mm Hg, and over two thirds of participants had been receiving hypertension treatment. The outcomes of interest, amongst others, included cardiovascular and all cause mortality, non fatal myocardial infarction, non fatal stroke and new or worsening renal or eye disease.
What interventions were examined in the research?
For six weeks before randomisation all participants received 2mg perindopril and 0.625mg indapamide, with all other treatments continuing at the discretion of the physician, apart from non perindopril ACE-inhibitors which were substituted for either 2mg or 4mg of perindopril. Participants who tolerated the treatment were then randomised to receive either 2mg perindopril and 0.625mg indapamide or placebo for three months. After three months the doses were doubled. During the trial concomitant drugs remained at the discretion of the physician, apart from non perindopril ACE inhibitors and thiazide diuretics, which were not allowed. Open-label perindopril was allowed to a maximum of 4mg per day, allowing a maximum total dose of 8mg perindopril in those randomised to active treatment. Participants were followed up at three, four, and at six months, and subsequently every six months. Mean follow-up of participants was 4.3 years.
What were the findings?
Overall participants who received perindopril and indapamide had significantly lower blood pressure than participants who received placebo, with a mean difference between the groups of 5.6mm Hg in systolic and 2.2mm Hg in diastolic blood pressure.
Participants who received perindopril and indapamide experienced a 14% risk reduction in all deaths (n=408 versus 471), 18% risk reduction in cardiovascular deaths (n=211 versus 257), 14% risk reduction in total coronary events (n=468 versus 535) and 21% reduction in total renal events (n=1243 versus 1500), compared to participants who received placebo. There was no statistically significant difference in risk of total cerebrovascular or total eye events between the intervention and control groups.
Subgroup analyses found broadly consistent treatment effects across variations in participant age, sex, history of vascular disease, ancillary treatments, and blood pressure at baseline.
What were the authors' conclusions?
Routine administration of a fixed combination of perindopril and indapamide given to patients with type 2 diabetes was well-tolerated and reduced the risks of major vascular events, including death. Results suggest that over five years, one death due to any cause would be averted for every 79 patients receiving active therapy.
How reliable are the conclusions?
This appears to be a large well designed randomised controlled trial with participants in the intervention and placebo arms well matched at baseline. The authors' results appear reliable however it is difficult to attribute the risk reduction in the treatment group only to taking perindopril and indapamide combination therapy when the concomitant treatments received by the intervention and placebo groups were allowed to change during the trial, which resulted in 55% of participants in the placebo group also receiving perindopril and 83% receiving a blood pressure lowering drug. The authors' conclusions appear to generalise the administration of perindopril and indapamide to all patients with type 2 diabetes, however the authors do acknowledge in the discussion that the provision of treatment should be based on assessment of vascular risk. The study findings were based on participants aged over 55 who had either a history of major cardiac disease or at least one other risk factor for cardiovascular disease, and who tolerated and adhered to the drug in the 6-week pre-randomisation phase. As such, the extent to which these findings can be generalised to others with type 2 diabetes is unclear.
Systematic reviews
Information staff at CRD searched for systematic reviews relevant to this topic. Systematic reviews are valuable sources of evidence as they locate, appraise and synthesize all available evidence on a particular topic.
There were no related systematic reviews identified on the Cochrane Database of Systematic Reviews (CDSR), however there were four on the Database of Abstracts of Reviews of Effects (DARE) (6-9).
References and resources
1. Cheap pill 'cuts deaths from diabetes'. Daily Telegraph, 3 September 2007, p6.
2. Diabetes treatment that could save 100,000 lives. Daily Mail, 3 September 2007, p12.
3. Diabetes pill could save 1m. Daily Express, 3 September 2007, p11.
4. ADVANCE Collaborative Group. Effects of a fixed combination of perindopril and indapamide on macrovascular and microvascular utcomes in patients with types 2 diabetes mellitus (the ADVANCE trial): a randomised controlled trial. Lancet Published online 2 September 2007. DOI:10.1016/S0140-6736(07)61303-8.
5. Kaplan NM. Vascular outcome in type 2 diabetes: an ADVANCE? Lancet Published online 2 September 2007. DOI:10.1016/S0140-6736(07)61304-X 1.
6. Turnbull F, Neal B, Algert C, Chalmers J, Chapman N, Cutler J, Woodward M, MacMahon S. Effects of different blood pressure-lowering regimens on major cardiovascular events in individuals with and without diabetes mellitus: results of prospectively designed overviews of randomized trials. Archives of Internal Medicine 2005;165(12)1410-1419. [DARE Abstract]
7. Gansevoort R T, Sluiter W J, Hemmelder M H, de Zeeuw D, de Jong P E. Antiproteinuric effect of blood-pressure-lowering agents: a meta-analysis of comparative trials. Nephrology Dialysis Transplantation 1995;10(11)1963-1974. [DARE Abstract]
8. Mancini G B. Long-term use of angiotensin-converting enzyme inhibitors to modify endothelial dysfunction: a review of clinical investigations. Clinical and Investigative Medicine 2000;23(2)144-161. [DARE Abstract]
9. Aminbakhsh A, Mancini G B. Chronic antioxidant use and changes in endothelial dysfunction: a review of clinical investigations. Canadian Journal of Cardiology 1999;15(8)895-903. [DARE Abstract]
Consumer information
Diabetes UK
NHS Direct - Diabetes
Previous Hitting the Headlines summaries on this topic
Beta blockers and diabetes. Hitting the Headlines archive, 7 September 2006.
Further information about Hitting the Headlines
Further information about Hitting the Headlines, together with selected relevant links, can be found at http://www.library.nhs.uk/hth/.
