This document summarizes a study that examined the risk of new diabetes with higher potency statins compared to lower potency statins. It discusses two previous meta-analyses that found a small increased risk of diabetes with statin use. The study analyzed administrative databases covering millions of patients and found a 15% higher rate of new diabetes over 2 years in those prescribed higher potency statins for secondary prevention of cardiovascular events compared to lower potency statins. Higher potency statins were associated with one additional case of diabetes for every 342 patients treated over 2 years. The increased risk was highest in the first 4 months of statin use.

1. Higher potency statins and
the risk of new diabetes
(multicentre, observational study of administrative databases)
Dormuth et al
BMJ Published 29 May 2014

2. INTRODUCTION
• Labels on statin medications in the United States now
include information concerning glycaemic effects,
including diabetes and increases in haemoglobin A1c
or fasting plasma glucose.
• The US Food and Drug Administration approved these
labelling changes in February 2012, based mainly on
evidence drawn from two meta-analyses of
randomised controlled trials.
• The first meta-analysis of statins compared with
placebo, conducted by Rajpathak and colleagues,
included 57 593 patients from six trials and showed a
small increase in risk for type 2 diabetes(relative risk
1.13).

3. • The second meta-analysis, reported by Sattar
and colleagues, examined the effect of statins on
the risk of diabetes in 91 140 patients from 13
trials. That meta-analysis showed that statins
were associated with a 9% increased risk of
diabetes (odds ratio 1.09).
• While statins are recommended for secondary
prevention of cardiovascular events in all
patients who tolerate treatment, the
incremental increase in diabetes risk with
higher potency statins compared with lower
potency statins remains to be determined.

4. • Existing clinical trials of statins were not
based on real world use, were not
specifically designed to assess diabetes
endpoints (and all had different and
informal ways of identifying diabetes), and
were not restricted to secondary
prevention of cardiovascular events, where
the potential benefit-risk profile is
different from that for primary prevention.

5. METHODS
Study population
• A common analytical protocol was used to
conduct population based cohort studies of
the association between statins and
diabetes in six provinces of Canada (source
population 13.2 million in 2013), as well as
in two international databases (the UK
Clinical Practice Research Datalink (CPRD),
population 11.6 million; and the US
MarketScan database, source population
about 70 million).

6. • The study populations were patients aged ≥40
years, without previously diagnosed or treated
diabetes, and newly prescribed a statin (no
prescription for a cholesterol lowering drug in
the year before hospitalisation) between 1
January 1997 and 31 March 2011 after a
hospitalisation for a major cardiovascular event
(myocardial infarction, stroke, coronary artery
bypass graft, or percutaneous coronary
intervention).

7. Data sources
• All eight participating sites analysed data from their
respective administrative healthcare databases, all
of which have been used previously for
observational research.
• All databases included information on the specific
drug dispensed in a prescription, the quantity or
days’ supply of medication dispensed , and the date
of dispensing.
• Patients who were missing demographic data were
not included in the analysis, and no imputation
methods were used.

8. Cohorts of statin treated patients
• As-treated analyses using nested case-control
methodology was used. Analyses were undertaken
separately at each site according to a common
analytical protocol and then meta-analytic
methods were used to estimate an overall rate
ratio.

9. • Secondary prevention cohorts, which included
patients who were admitted to a hospital between 1
January 1998 (or one year after the beginning of
data availability) and 31 March 2011, who received a
coded diagnosis for acute myocardial infarction or
stroke or a procedure for coronary artery bypass
graft or percutaneous coronary intervention during
their stay in hospital, who had no record of a
diabetes diagnosis during their hospitalisation, and
who then received a statin prescription within 90
days after being discharged, having not been
prescribed a cholesterol lowering drug in the
previous year were assembled

10. • Patients were required to have a length of stay in
hospital for their cohort-defining event or procedure
of at least three days and no greater than 30 days.
• Patients’ cohort entry dates were defined as the date
of the first statin prescription after discharge from
hospital.
• Patients if they were <40 years old, had less than
one year of database history, received any
cholesterol lowering drug, or received any diabetes
medication or a diabetes diagnosis in the previous
year, including diagnoses during their index
hospitalisation were excluded.

11. • Rosuvastatin ≥10 mg, atorvastatin ≥20 mg, and
simvastatin ≥40 mg as higher potency statins,
and all other statins were defined as lower
potency statins.
• Therefore, statins were categorised as higher or
lower in the study according to whether they
would produce a theoretical <45% or ≥45%
reduction in LDL cholesterol concentration.
• In the analysis, high dimensional propensity
scores were used to estimate the predicted
probability (propensity score) of exposure to
higher potency statins versus lower potency
statins, conditional on all of the included
covariates.

12. RESULTS
Study populations
• Overall, there were in excess of two million patients
in participating databases newly exposed to statins
during the study period.
• The mean age of study participants was 68 years,
and 63% were men.
• After restricting the analysis to patients newly
dispensed statins within 90 days of a hospitalisation
for myocardial infarction, stroke, coronary artery
bypass graft, or percutaneous coronary intervention,
and after trimming the 10% of patients with the
most extreme propensity scores, there were 136 936
patients who remained eligible for further analysis.

13. • Baseline characteristics of the overall study
population were matched on propensity score.
Diabetes events
• In total, there were 3629 cases of new onset
diabetes in the first two years of follow-up in the
study population of 136 966 patients.

14. As-treated analyses
• For current cumulative exposure within two
years, a 15% higher rate of diabetes was observed
in patients prescribed higher potency statins
compared with patients prescribed lower
potency statins.
• An estimated 342 secondary prevention
patients needed to be treated with a higher
potency statin instead of a lower potency statin
for two years to cause one additional case of
diabetes.
• The risk increase seemed to be highest in the
first four months of statin use.

15. DISCUSSION
• In this study of over 136 936 patients
hospitalised for a major cardiovascular event or
procedure, a group in which statin treatment is
strongly indicated for secondary prevention, a
moderately increased risk of new onset diabetes
in patients prescribed higher potency statins was
observed compared with lower potency statins.

16. • The increased risk warrants careful
consideration given that randomised controlled
trials making head to head comparisons of
higher potency and lower potency statins in
patients with stable coronary heart disease
showed no difference in all cause mortality or
serious adverse events.

17. • Multiple trials have shown that the risk of all cause mortality is
reduced in patients treated with a statin for secondary
prevention of cardiovascular events instead of placebo, but the
risk of all cause mortality was equally likely in trials that
directly compared higher potency and lower potency statins in
patients with stable coronary heart disease. Serious adverse
events were also equally likely, and withdrawals from
treatment due to adverse events were more likely in patients
prescribed higher potency statins.
• Pedersen T et al. High-dose atorvastatin vs usual-dose simvastatin for
secondary prevention after myocardial infarction. JAMA 2005;294:2437-
45.
• LaRosa J et al. Intensive lipid lowering with atorvastatin in patients with
stable coronary heart disease. N Engl J Med 2005;352:1425-35.
• Rahimi K, et al. Intensive lowering of LDL cholesterol with 80 mg versus 20
mg simvastatin daily in 12 064 survivors of myocardial infarction: a
double-blind randomized trial. Lancet 2010;376:1658-69.

18. Comparison with existing evidence
• The overall rate ratio for current treatment that
we observed in the analysis of statins and
diabetes (rate ratio 1.15) was similar to the
relative risks reported in the meta-analyses by
Rajpathak et al (relative risk 1.13), by Sattar et al
(odds ratio 1.09), and by Preiss et al in a meta-analysis
of trials comparing higher potency and
lower potency statins (odds ratio 1.12).
• The study was specifically designed to examine a
hypothesis that the risk of new onset diabetes
was associated with statin potency.

19. • While there are several plausible mechanisms
consistent with a potency hypothesis, other
distinct hypotheses have also been advanced,
such as an effect related to hydrophylic/lipophylic
status of each statin, or a statin-specific effect.
• The results do not lend support to a
hydrophylic/lipophylic hypothesis because the
two hydrophylic statins (pravastatin and
rosuvastatin) are at near opposite ends of the
potency spectrum in their effect on serum LDL
cholesterol.

20. • The results are somewhat compatible with other
research that showed an increased diabetes risk
with rosuvastatin, atorvastatin, and simvastatin.
Although potency and statin-specific
mechanisms are distinctly different hypothesis,
the results might be expected to be compatible
because the specific statins associated with an
increased risk above are also the three most
potent statins.
Carter AA, Gomes T, Camacho X, Juurlink DN, Shah BR,
Mamdani MM. Risk of diabetes among patients treated with
statins: population based study. BMJ 2013;346:f2610.

21. METHODICAL CONSIDERATIONS
• The diabetes outcome definition in this study,
consisting of a diagnosis of diabetes in a hospital
admission or a prescription for a diabetes
medication, probably did not capture some
patients diagnosed in an ambulatory setting but
not treated with pharmacotherapy.
• Ascertaining diabetes from physician claims
data typically requires multiple visits over a
number of months in order to remove false
positives. The study excluded such potential
cases from the outcome definition to avoid
potential bias in the rate ratio.

22. • As with many other diseases in observational
research, the date of a first encounter with the
healthcare system that coincides with the first
recorded occurrence of the disease is used as a
proxy for the timing of disease onset. Further,
the endpoint was defined as the date of a first
antidiabetic prescription in many cases, which
would have required a prior diagnosis of
diabetes.
• The study was adjusted for a broad spectrum of
possible confounders using high dimensional
propensity scores, which included both pre-specified
and empirically identified confounders.

23. CONCLUSIONS
• The study found modest evidence that there is a harmful
association between statin potency and new diabetes in
patients treated for secondary prevention of
cardiovascular disease.
• Clinicians should consider the study results when
choosing between lower potency and higher potency
statins in secondary prevention patients, perhaps bearing
in mind that head to head randomised trials of higher
potency versus lower potency statins have not shown a
reduction in all cause mortality or serious adverse events
in secondary prevention patients with stable disease.

24. 28th february 2012
A meta-analysis by Rajpathak et al.,20 which included 6 statin trials with
57,593 FDA’s participants, review of the also results reported from the a small Justification increase for in diabetes the Use of
risk
(Statins relative in risk Primary [RR] 1.13; Prevention: 95% CI 1.03-an Intervention 1.23), with no Trial evidence Evaluating
of
heterogeneity Rosuvastatin across (JUPITER) trials. reported A recent a study 27% increase by Culver in et investigator-reported
al.,26 using data
from the Women’s diabetes mellitus Health Initiative, in rosuvastatin-reported treated that statin patients
use conveys an
increased risk of new-onset diabetes in postmenopausal women, and
noted that the effect appears to be a medication class effect, unrelated to
potency or to individual statin.
Based on clinical trial meta-analyses and epidemiological data from the
published literature, information concerning an effect of statins on
incident diabetes and increases in HbA1c and/or fasting plasma glucose
was added to statin labels.
compared to placebo-treated patients. High-dose atorvastatin had
also been associated with worsening glycemic control in the
Pravastatin or Atorvastatin Evaluation and Infection Therapy –
Thrombolysis In Myocardial Infarction 22 (PROVE-IT TIMI 22)
substudy. FDA also reviewed the published medical literature. A
meta-analysis by Sattar et al.,19 which included 13 statin trials with
91,140 participants, reported that statin therapy was associated with
a 9% increased risk for incident diabetes (odds ratio [OR] 1.09; 95%
confidence interval [CI] 1.02-1.17), with little heterogeneity
(I2=11%) between trials.

25. • Rajpathak et al performed a meta-analysis,
published in 2009, of six trials—WOSCOPS,
ASCOT-LLA, JUPITER, HPS, the Longterm
Intervention With Pravastatin in Ischaemic Disease
(LIPID) study, and the Controlled Rosuvastatin
Multinational Study in Heart Failure (CORONA),
with a total of 57,593 patients. They calculated that
the incidence of diabetes was 13% higher in statin
recipients, which was statistically significant
• Sattar et al, in a larger meta-analysis
published in 2010, included 91,140 participants in
13 major statin trials conducted between 1994 and
2009; each trial had more than 1,000 patients and
more than 1 year of follow-up.

26. New diabetes occurred in 2,226 (4.89%) of the
statin recipients and in 2,052 (4.5%) of the
placebo recipients, an absolute difference of
0.39%, or 9% more (odds ratio [OR] 1.09; 95%
confidence interval [CI] 1.02–1.17). The
incidence of diabetes varied substantially among
the 13 trials, with only JUPITER and PROSPER
finding statistically significant increases in rates
(26% and 32%, respectively).

27. Possible Explanations,
but no unifying mechanism
• If mechanisms could be identified to explain the
association between statins and diabetes, this
would strengthen the argument that it is a cause-and-
effect relationship. Many explanations have
been proposed as to how statins may influence
glucose metabolism and insulin sensitivity.
• In theory, statins may improve insulin sensitivity
via their anti-inflammatory effect, since
inflammatory markers and proinflammatory
cytokines have been linked with insulin
resistance.

28. • However, other effects of statins may adversely
affect glycemic control. In vivo analysis has
shown that some but not all statins increase
insulin levels and decrease insulin sensitivity in
a dose-dependent fashion. Some statins decrease
adiponectin and may worsen glycemic control
through loss of adiponectin’s proposed
protective antiproliferative and antiangiogenic
properties.

29. • In vitro studies and animal studies have
demonstrated a decrease in expression of insulin
responsive glucose transporter 4 (GLUT4) with
atorvastatin. It has been hypothesized that
reduction in isoprenoid biosynthesis or
decreased insulin signaling may explain these
effects and that changes in glucose transport in
adipocytes may cause insulin resistance.
• Other studies suggest that dysregulation of
cellular cholesterol may attenuate beta-cell
function. Impaired biosynthesis of ubiquinones
may result in delayed production of adenosine
triphosphate and consequently diminish insulin
release.

30. Does the specific statin
make a difference to the
risk of NOD? • Various studies suggest that factors such as using
hydrophilicity (pravastatin and rosuvastatin) or
lipophilicity (atorvastatin, lovastatin, pitavastatin
and simvastatin) may influence the risk of NOD
from statin therapy .
• Yamakawa et al. examined the effect of atorvastatin
10 mg/day, pravastatin 10 mg/day, and pitavastatin
2 mg/day on glycemic control over 3 months in a
retrospective analysis. Random blood glucose and
HbA1c levels were increased in the atorvastatin
group but not in the other two .

31. • A prospective comparison of atorvastatin 20 mg
vs pitavastatin 4 mg in patients with type 2 DM,
showed a significant increase in fasting glucose
levels with atorvastatin, particularly in women,
but not with pitavastatin.
• In the Compare the Effect of Rosuvastatin With
Atorvastatin on Apo B/Apo A-1 Ratio in Patients
With Type 2 Diabetes Mellitus and
Dyslipidaemia (CORALL) study, both high-dose
rosuvastatin(40 mg) and high-dose atorvastatin
(80 mg) were associated with significant
increases in, although the mean fasting glucose
levels were not significantly different at 18 weeks
of therapy .

32. • A meta-analysis by Sattar et al. did not find a clear
difference between lipophilic statins (OR 1.10 vs
placebo) and hydrophilic statins (OR 1.08). In
analysis by statin type, the combined rosuvastatin
trials were significant in favor of a higher DM risk
(odds ratio[OR]: 1.18; 95%CI; 1.04-1.44).
Insignificant trends were noted for atorvastatin trials
(OR: 1.14) and simvastatin trials (OR: 1.11) and less
so for pravastatin (OR: 1.03); the OR for lovastatin
was 0.98.
• This may suggest that there is a stronger effect with
more potent statins or with greater lowering of LDL-C.
Furthermore, this evidence does not support a
protective or neutral role for statin hydrophilicity in
the pathogenesis of NOD.

33. Dose-relationship between statins
and NOD
• Preiss et al. in 2011 performed a meta-analysis of
the impact of intensity of statin therapy on DM risk.
They examined data from 32752 participants
without DM at baseline in 5 randomized controlled
trials with more than 1 000 participants and > 1 year
of follow-up, comparing high-dose therapy against
moderate-dose statin therapy.
• DM developed in 1449 (8.8%) of the intensive-therapy
group and 1300 (8.0%) of the moderate-therapy
group.
Preiss D, Seshasai SR, Welsh P, et al. Risk of incident diabetes with intensive-dose compared with
moderate-dose statin therapy: a meta-analysis. JAMA 2011; 305: 2556-64

34. Balancing the benefits and
risks of statins
• Preiss et al. calculated that there were 2 more cases of
DM per 1000 patient-years in patients receiving
intensive doses than in those receiving moderate doses
(18.9 vs 16.9), corresponding to 1 additional case of DM
for every 498 patients treated per year. However, there
were 6.5 fewer first major CV events per 1 000 patient
years (44.5 vs 51.0), corresponding to a number needed
to treat per year to prevent 1 CV event of 155. Most of the
benefit was due to fewer revascularizations, followed by
nonfatal myocardial infarctions. The 12% increase in
NOD with high-dose therapy contrasted with a 16%
reduction in new CVD combined events. According to
this study, intense statin treatment is beneficial since it
outweighs the risk of NOD.

35. People with diabetes need
aggressive
l•ipDiiadb-etelso isw ae corroinnagry heart disease risk equivalent and
is associated with high risk of cardiovascular events.
Overall, the risk for these adverse events is two to four
times greater in people with diabetes than without.
• Atherosclerosis-related events account for approximately
65% to 75% of all deaths in people with diabetes, and
75% of these events are coronary. Lipid abnormalities
are strongly correlated with the risk of cardiovascular
disease in people with diabetes, and aggressive
treatment of risk factors, particularly lipid abnormalities,
has been shown to reduce this risk. And data from
multiple clinical trials support the use of statins to lower
LDL-C as the first-line therapy for dyslipidemia in
people with diabetes, just as it is in the general
population.

36. “ A high level of evidence supports the use of moderate-intensity statin
“Statins modestly increase the excess risk of type-2 diabetes in
individuals with risk factors for diabetes. The potential for an ASCVD
risk reduction benefit outweighs the excess risk of diabetes in all but
the lowest risk individuals. All individuals receiving statins should be
counseled on healthy lifestyle habits. Individuals receiving statin
therapy should be evaluated for new-onset diabetes according to the
current diabetes screening guidelines. Those who develop diabetes
during statin therapy should be encouraged to adhere to a heart
healthy dietary pattern, engage in physical activity, achieve and
maintain a healthy body weight, cease tobacco use, and continue
statin therapy to reduce their risk of ASCVD events”
therapy in persons with diabetes 40 to 75 years of age. The only trial
of high-intensity statin therapy in primary prevention was
performed in a population without diabetes. However, a high level
of evidence was considered for event with statin therapy reduction
in individuals with a ≥7.5% estimated 10-year ASCVD risk who did
not have diabetes to recommend high-intensity statin therapy
preferentially for individuals with diabetes and a ≥7.5% estimated
10-year ASCVD risk. This consideration for those with diabetes 40
to 75 years of age recognizes that these individuals are at
substantially increased lifetime risk for ASCVD events and death.In
persons with diabetes <40 or >75 years of age, statin therapy should
be individualized based on considerations of ASCVD risk reduction
benefits, the potential for adverse effects and drug-drug
interactions, and patient preferences.

38. The association is real, but questions remain
• In view of the evidence, it is difficult to
refute that an association exits between
statin use and new-onset diabetes, at least
in some subgroups. The dose response noted
in some studies further reinforces the
conclusion that the association is real.
• However, many questions remain unanswered
regarding mechanism of effect, whether
there are differences depending on the
particular statin or dose used, or
differential effects in the populations
treated.

39. • From a clinical standpoint there is no
current evidence suggesting that the
elevations in blood glucose seen while on
lipid lowering or blood-pressure-lowering
therapy are associated with an increased
risk of cardiovascular events or that they
attenuate the beneficial effects of the
therapy.
• Until further studies are carried out,
statins should continue to be used, after
careful assessing the risks and benefits for
individual patients.
• Primary prevention patients at moderate to
high risk and secondary prevention patients
stand to gain from statin therapy, and it
should not be denied or doses reduced on the
basis of concerns about the development of
NOD.

40. • Furthermore, it is important to keep in mind
that statins are highly effective in
individuals with type 2 DM. Current data do
not support the discontinuation of statins
when DM is diagnosed, and it remains prudent
to target lipid levels according to
established guidelines.
• Statins should be considered individually for
each patient only in case of lifestyle
interventions failure. The small absolute
increase in DM risk and the proven clinical
utility of statins in primary and secondary
prevention require clinicians to weight the
risk and benefit of statin therapy for any
given patient.

41. Clinicians should monitor glucose and/or HbA1c
in patients with multiple risk factors for DM
who take statins, but they should continue to
prescribe statins when indicated as part of a
multifactorial approach to managing CV risk.
A major take-home message for the clinician
involved in either primary or secondary
prevention of CVD is that all individuals on a
statin who have major risk factors for DM,
particularly impaired fasting glucose, need to
be informed about the risk, monitored
regularly for hyperglycemia, and advised to
lose weight and perform regular physical
exercise to mitigate the emergence of DM.

42. Thank You