Under embargo until 00:01 London time on Wednesday 24 September 2014 / 19:01 US Eastern time
on Tuesday 23 September 2014
HMG-CoA reductase inhibition, type 2 diabetes and body weight: evidence from
genetic analysis and randomised trials
Summary of key messages
Swerdlow DI et al., HMG-coenzyme A reductase inhibition, type 2 diabetes, and bodyweight: evidence from genetic analysis
and randomised trials, will be published in The Lancet at the following URL: http://dx.doi.org/10.1016/S01406736(14)61183-1
What is already known?
About statin action:
• Statins lower low density lipoprotein (LDL)-cholesterol by inhibiting the action of the liver enzyme HMG-CoA
reductase.
About statin benefits:
• Based on evidence from large randomised controlled trials (RCTs), statins have been shown to reduce risk of fatal
and non-fatal heart attacks and ischaemic stroke (major vascular events) in proportion to the degree of LDLcholesterol lowering.
• Statin treatment is considered beneficial in patients with established cardiovascular disease and in people without
clinically evident cardiovascular disease whose 10-year risk of a future vascular event is 10% (10 in 100) or higher
(approximately equivalent to a 5-year risk of 5% or higher).
• The absolute benefit of statin treatment depends on the baseline cardiovascular disease risk: for example, for an
individual with a 5-year absolute risk of major vascular events of 10%, statin treatment at a dose that reduces
circulating LDL-cholesterol concentration by about 1mmol/L, might be estimated to reduce the risk of major
vascular events by about one-fifth, from 10% to 8%. Larger LDL-cholesterol reductions or longer durations of statin
treatment might be expected to confer greater benefit.
About statins and type 2 diabetes:
• Statins reduce cardiovascular events among patients with, as well as those without established type 2 diabetes.
• Based on evidence from RCTs, statin treatment is associated with a small increase in risk of new-onset type 2
diabetes.
• The modest risk of developing type 2 diabetes during statin treatment is outweighed by the larger reduction in
cardiovascular events.
• It has been uncertain if the effect of statins on type 2 diabetes risk is an on-target action (due to inhibition of HMGCoA reductase) or an off-target effect (through effects on a different biological pathway).
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What this study adds:
New information on risk of new-onset type 2 diabetes from statin treatment
• Based on an updated analysis of information from RCTs, statins increase the risk of new-onset diabetes by about
12% over approximately 4 years of follow-up.
• For example, an individual who has a 4.5% (4.5 in 100) risk of developing type 2 diabetes in the absence of statin
treatment over around 5 years, the risk could increase to approximately 5% (5 in 100) as a result of statin
treatment.
New information from RCTs on the mechanism by which statins increase risk of type 2 diabetes
• In RCTs, those receiving statins had a body weight at trial termination higher on average by about 0.24kg (approx
0.5lb) when compared to the control group.
New evidence that the effect of statins on type 2 diabetes risk is on-target
• In genetic association studies, two common sequence variations in the gene encoding the intended
pharmacological target of statins (HMGCR) were examined, the inheritance of which is randomised like drug
treatment in a RCT. These variants were associated with lower circulating LDL-cholesterol.
• Carriage of the same genetic variants was associated with a small but discernible increase in the risk of type 2
diabetes, higher blood glucose and insulin, and higher body weight.
What are the main interpretations of the findings?
•
•
The concordance of findings from RCTs and genetic studies suggests that the effect of statins on the risk of newonset type 2 diabetes is an on-target effect, i.e. results from inhibition of HMG-CoA reductase.
Since a higher body weight is known to increase risk of type 2 diabetes, this may provide one explanation for the
modestly higher risk of new-onset type 2 diabetes from statin treatment.
What (if any) implications do the findings have for clinical practice and population health?
•
•
•
•
•
The motivation for the study was to investigate the mechanisms underlying the known relationship between statin
treatment and higher type 2 diabetes risk.
The study does not relate to the use of information on an individual's genetic makeup to predict clinical response
to statin treatment.
The differences in diabetes risk and weight gain observed in the analysis of statin trials were of a modest degree
that might be readily mitigated by adoption of a healthy diet and lifestyle.
Doctors prescribing statins should continue to emphasise the importance of a healthy diet and physical activity
alongside statin therapy, which may not only mitigate any modest effect of statins on diabetes risk but could also
further enhance the benefit of statin treatment in protecting from heart attacks or strokes.
Statins should continue to be prescribed according to current guidelines.
Notes to Editors
For a copy of the paper, or to speak to Dr Swerdlow or Professor Hingorani, contact Harry Dayantis in the UCL press office,
T: +44(0)20 3108 3844, M: +44(0)7747 565056, E: h.dayantis@ucl.ac.uk
To speak to Dr Preiss or Professor Sattar, contact Stuart Forsyth in the University of Glasgow press office, T: +44(0)141 330
4831, M: +44(0)7854 034 342, E: Stuart.Forsyth@glasgow.ac.uk
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