Improved management of population cardiovascular risk in diabetic patients
Submitting InstitutionUniversity of Manchester
Unit of AssessmentClinical Medicine
Summary Impact TypeHealth
Research Subject Area(s)
Medical and Health Sciences: Cardiorespiratory Medicine and Haematology, Clinical Sciences, Public Health and Health Services
Summary of the impact
The Collaborative Atorvastatin Diabetes Study (2004), led by researchers
at the University of Manchester (UoM), established the efficacy of statin
therapy in the prevention of atherosclerotic cardiovascular disease (CVD)
among patients with diabetes. The research challenged the previously held
view that, since CVD risk is markedly raised in people with diabetes even
when blood cholesterol levels are normal, statins were unlikely to be
beneficial for this group. These key findings have informed clinical
guidelines governing the use of statin therapy in the UK (NICE, SIGN) and
internationally (American Heart Association and the American Diabetes
Association, ESC, EAS), ensuring that statins are now considered for all
See section 3 for references 1-6. UoM researchers are given in bold.
A number of trials (e.g., Scandinavian Simvastatin Survival Study, Lancet
1994) established the value of statins in preventing CVD in non-diabetic
patients. However, diabetologists were reluctant to extrapolate this
evidence to diabetic patients because diabetes does not typically cause
raised cholesterol. In addition there were earlier adverse experiences
with less effective and possibly harmful lipid-lowering medication and a
disinclination to add to complex treatment regimens for glycaemia and
blood pressure control.
Collaborative Atorvastatin Diabetes Study (CARDS)
Key researchers at UoM:
Paul Durrington (Professor of Medicine, 1995-2009; Honorary
Professor of Medicine, 2009-date)
Michael Mackness (Research Fellow, 1998-1999; Lecturer,
1999-2002; Senior Research Fellow, 2002-2003; Reader, 2003-2008)
Valentine Charlton-Menys (Research Associate, 1999-2010)
Michael France (Honorary Lecturer, 2007-date)
Durrington and Fuller (University of London) raised funding from
Diabetes UK (DUK) to convene a committee to design a trial of lipid
lowering specifically in type 2 diabetes. The committee comprised the
Director of R and D from DUK, a representative of the Department of Health
(DH), Neil (Oxford), Hitman (London) and Betteridge (London). A large,
scientifically rigorous trial was designed, with substantial funding
provided by industry as well as DH and DUK. Parke Davies provided funding,
atorvastatin and placebo. Durrington led the central laboratory,
which was managed initially by Mackness and later by Charlton-Menys.
Durrington also joined the Steering Committee.
After a pilot investigation in secondary prevention, the key trial to
test the hypothesis that in primary prevention a statin could decrease CVD
risk began in 1998. By then, it was becoming obvious from transnational
epidemiology that there was no lower threshold below which low-density
lipoprotein (LDL) ceased to be a risk factor for CVD. Therefore the target
of the new primary prevention study was aimed at patients with lower LDL
levels. The participants were 2838 type 2 diabetic patients with LDL
cholesterol ≤4.14mmol/l and no clinical evidence of CVD, attending 132
centres in the UK and Ireland. They had at least one risk factor for CVD
besides diabetes, most commonly mild hypertension.
- The trial was terminated in 2003 after 3.9 years (2 years early) by
the Safety Monitoring Committee because of a substantial highly
significant lower CVD event rate on the active treatment.
- The mean pre-treatment LDL cholesterol was 3mmol/l and the average
decrease on atorvastatin was 1.2mmol/l (1). This produced a 37% decrease
in CVD incidence (P<0.001) due to reductions of 36% in acute coronary
events, 31% in coronary revascularisation and 48% in stroke (2-5).
- All-cause mortality declined by 27%, which just failed to reach
statistical significance (P=0.059) for the whole trial, but was highly
significant in its final year (2).
- Adverse active treatment effects were no more frequent than on placebo
(for example, albuminuria incidence was not increased, 6).
The CARDS database and biobank (created in Manchester), which includes DNA,
serum and urine, continues to generate significant scientific findings about
aspects of atherosclerosis and metabolic responses to statin treatment.
References to the research
1. Colhoun HM, Betteridge DJ, Durrington PN, Hitman GA, Neil HA,
Livingstone SJ, Thomason MJ, Mackness MI, Charlton-Menys V,
Fuller JH on behalf of the CARDS Investigators. Primary prevention of
cardiovascular disease with atorvastatin in Type 2 diabetes in the
Collaborative Atorvastatin Diabetes Study (CARDS); a multicentre
randomised placebo controlled trial. Lancet. 2004; 364: 685-96.
2. Colhoun H, Betteridge DJ, Durrington PN et al. Rapid emergence
of effect of atorvastatin on cardiovascular outcomes in the Collaborative
Atorvastatin Diabetes Study (CARDS). Diabetologia. 2005; 48:
2482-2485. DOI: 10.1007/s00125-005-0029-y
3. Raikou M., McGuire A., Colhoun HM, Betteridge DJ, Durrington PN,
Hitman GA, Neil HAW, Livingstone SJ, Charlton-Menys V, Fuller JH.
Cost effectiveness of primary prevention of CVD with atorvastatin in type
2 diabetes: results from the Collaborative Atorvastatin Diabetes, Study
(CARDS). Diabetologia. 2007; 50: 733-740. DOI:
V, Betteridge DJ, Colhoun H, Fuller J, France M, Hitman
GA, Livingstone SJ, Neil HA, Newman CB, Szarek M, Demicco DA, Durrington
PN. Apolipoproteins, cardiovascular risk and statin response
in type 2 diabetes: the Collaborative Atorvastatin Diabetes Study (CARDS).
Diabetologia. 2009; 52: 218-225. DOI: 10.1007/s00125-008-1176-8
5. Charlton-Menys V, Betteridge DJ, Colhoun H, Fuller J, France
M, Hitman GA, Livingstone SJ, Neil HA, Newman CB, Szarek M, DeMicco
DA, Durrington PN. Targets
of statin therapy: LDL cholesterol, non-HDL cholesterol, and
apolipoprotein B in type 2 diabetes in the Collaborative Atorvastatin
Diabetes Study (CARDS). Clinical Chemistry. 2009;55:473-80.
Details of the impact
See section 5 for corroborating sources S1-S10.
Context and pathways to impact
Statistics published by DUK show that CVD is the cause of death in 52% of
people with type 2 diabetes and 44% with type 1. Within 5 years of its
onset (and many people are not diagnosed until then) CVD risk in type 2
diabetes is the same as in non-diabetic people who have already had a
myocardial infarction. The additional risk is higher still in diabetic
compared with non-diabetic women. Within 5 years of diagnosis stroke risk
is doubled. The publication of CARDS in 2004 (1) therefore attracted great
interest both in scientific journals and lay press. The initial Lancet
report has over 2500 citations, and DUK set new target levels of LDL
cholesterol of <2mmol/l, to be achieved with statins if necessary,
which were widely broadcast.
Reach and significance of the impact
Impact on national and international clinical guidelines
Following publication of the findings, DUK rapidly ensured that new
guidelines for statin use in diabetes were incorporated in the Joint
British Societies second recommendations (JBS2, 2005) (S1). The
recommendations state that all type 2 diabetic patients aged ≥40 years
(and also some younger patients with particularly adverse risk factors)
should receive statin treatment to achieve an LDL cholesterol <2mmo/l.
The DUK recommendations were further extrapolated to include type 1
diabetes, but this was on the basis of their CVD risk and the practicality
of implementation when the distinction between the two types was often
blurred in general practice.
The British Heart Foundation endorsed the JBS2 recommendation (S2), but
the Association of British Clinical Diabetologists (ABCD) was one of a
number of groups to challenge the CARDS conclusions. The arguments were
that the patients randomised in CARDS were atypical, particularly in their
high CVD risk. In fact, they were subsequently shown to be at high risk,
but no more than typical diabetic patients. There was initial reluctance
to accept that an apparently low LDL cholesterol target for statin
treatment was justified by CARDS. In fact, in CARDS the mean LDL
cholesterol had been decreased from around 3mmol/l (the average in
middle-aged Britons is 3.7mmol/l) to under 2mmol/l.
These arguments were overcome and the guidance issued by ABCD, NICE and
SIGN (2007-2010) (S3, S4) is essentially the same as JBS2
(S1). The guidance was strengthened by a meta-analysis by Kearney and
colleagues largely drawing on data from CARDS and the Heart Protection
Study, which was a mixed primary and secondary trial of the less effective
simvastatin, and which included a diabetic cohort (S5).
North American guidelines were modified to take account of the new
evidence provided by CARDS (S6) and European recommendations rapidly
followed (S7, S8).
Improved management of diabetes
The acceptance of the CARDS findings is now universal and statins are an
essential part of diabetic management. Indeed statin targets are generally
easier to achieve than recommended goals for glycaemia or blood pressure.
Proof of benefit and evidence of cost-effectiveness is stronger for statin
therapy than any other aspect of type 2 diabetes management (S9).
The full impact of CARDS on global health is difficult to evaluate
precisely, but it is likely to be vast. Many of the 400 million people
with diabetes globally inhabit countries that are not affluent. However,
now that both simvastatin and atorvastatin are out of patent, many more of
the 2 million CVD deaths occurring annually in diabetes worldwide should
be preventable (S10).
Sources to corroborate the impact
S1.Joint British Societies' Guidelines on Prevention of Cardiovascular
Disease in Clinical Practice (JBS2). Heart. 2005; 91 Suppl V: 1-52
S2.British Heart Foundation Factfile Jan 2006: Joint British Societies'
Guidelines on Prevention of Cardiovascular Disease in Clinical Practice:
Risk Assessment. http://www.bhsoc.org/files/5013/3363/9191/Factfile_2006_JBS2_Guidelines_on_the_Prevention_of_Cardiovascular_Disease_in_Clinical_Practice.pdf
S3.Feher MD, Winocour PH. On behalf of the Association of British
Clinical Diabetologists (ABCD). ABCD position statement on lipid modifying
drug therapy in diabetes. Practical Diabetes International. 2007;
24: 458-462 (published jointly with Scottish Intercollegiate Guidelines
Network). See SIGN 116 Management of diabetes. Summary of recommendations.
S4.National Institute for Health and Clinical Excellence (NICE) clinical
guideline 67. Lipid modification. Cardiovascular risk assessment and the
modification of blood lipids for the primary and secondary prevention of
cardiovascular disease. Developed by the National Collaborating Centre for
Primary Care. Issue date: May 2008 (reissued March 2010) http://www.nice.org.uk/nicemedia/pdf/CG67NICEguideline.pdf
S5.Kearney PM, Blackwell L, Collins R, Keech A, Simes J, Baigent C,
Cholesterol Treatment Trialists' (CTT) Collaborators. Efficacy of
cholesterol-lowering therapy in 18,686 people with diabetes in 14
randomised trials of statins: a meta-analysis. Lancet. 2008; 371:
117-25. DOI: 10.1016/S0140-6736(08)60104-X
S6.Buse JB., Ginsberg HN., Bakris GL et al. Primary prevention of
cardiovascular disease in people with diabetes mellitus: a scientific
statement from the American Heart Association and the American Diabetes
Association. Circulation. 2007; 115: 114-126 DOI: 10.1161/
I Atar D, Borch-Johnsen K et al. European guidelines on
cardiovascular disease prevention in clinical practice: executive summary.
Joint Task Force of the European Society of Cardiology and Other
Societies on Cardiovascular Disease Prevention in Clinical Practice. European
Heart Journal. 2007;28: 2375-2414. DOI:
S8.Catapano AL et al. ESC/EAS Guidelines for the management of
dyslipidaemias, The Task Force for the management of dyslipidaemias of the
European Society of Cardiology (ESC) and the European Atherosclerosis
Society (EAS). European Heart Journal. 2011; 32: 1769-818 DOI:
10.1093/eurheartj/ehr158 and Atherosclerosis. 2011; 217: 3-46.
S9.Annemanns L, Marbaix S, Webb K et al. Cost effectiveness of
atorvastatin in patients with type 2 diabetes mellitus: a pharmacoeconomic
analysis of the collaborative atorvastatin diabetes study in the Belgian
population. Clinical Drug Investigation. 2010; 30: 133-42. DOI:
S10.International Diabetes Federation. Global Guideline for Type 2
Diabetes (2012). www.idf.org/sites/default/files/IDF-Guideline-for-Type-2-Diabetes.pdf