1. Statin s and
Diabet es
between risks and benefits
Alexandru Andritoiu
Military Hospital Craiova, MD, MPh

2. Drugs that induce diabetes
Drugs that cause diabetes by interfering with insulin production and secretion
Vacor
Tacrolimus
Didansoine
β-receptor antagonists
L-asparaginase
Diphenylhydantoin
Diazoxide
Drugs that cause diabetes by reducing the effectiveness of insulin to regulate metabolism
Steroids
Glucocorticoids
Megasterol acetate
β-receptor agonists
Growth hormone
Protease inhibitors
Drugs that act on both insulin secretion and insulin sensitivity
Thiazide diuretics
Cyclosporine
Atypical antipsychotic medications
Treatments that induce diabetes by increasing nutrient flux
Nicotinic acid
Total parenteral nutrition
Richard J Coli D. Diabetes Melitus: A Fundamental and Clinical Text. 3rd Edition 2004

3. FDA Expands Advice on Statin Risks
(2012)




Routine monitoring of liver enzymes in the blood, once considered
standard procedure for statin users, is no longer needed. Such
monitoring has not been found to be effective in predicting or
preventing the rare occurrences of serious liver injury associated
with statin use.
Cognitive (brain-related) impairment, such as memory loss,
forgetfulness and confusion, has been reported by some statin
users.
People being treated with statins may have an increased risk of
raised blood sugar levels and the development of Type 2
diabetes.
Some medications interact with lovastatin (brand names include
Mevacor) and can increase the risk of muscle damage.

4.  FDA Adds Diabetes, Memory Loss Warnings to Statins Reuters
 Safety Alerts Cite Cholesterol Drugs’ Side Effects The New York
Times
 Statin Labels will Come with New Safety Warnings CNN
 FDA Adds Safety Warnings to Statins HealthDay
 FDA Adds Diabetes Warning to Statin Label MedPage Today

5. To prescribe or not to prescribe:
That is the statin question
Blumenthal RS. Redberg R.
Should healthy people take cholesterol drugs to prevent
heart disease? Wall Street Journal, January 23, 2012.

8. The Diabetes Dilemma for Statin Users
ERIC J. TOPOL
Published: March 4, 2012
,,We need to find out why statins cause diabetes and, ideally,
through genomics we could determine who is at risk for this
important side effect.
But to date nothing has been done to sort this out — despite
the fact that the market for statins is well over $20 billion per
year.
There are thousands of blood samples sitting in company
freezers around the world that could potentially provide the
answers”

10. The Lancet, Volume 380, Issue 9841,
Pages 565 - 571, 11 August 2012
Cardiovascular benefits and diabetes
risks of statin therapy in primary
prevention: an analysis from the
JUPITER trial
Paul M Ridker, et al

11. In the JUPITER primary prevention trial,
the cardiovascular and mortality benefits
of statin therapy exceed the diabetes
hazard, including in participants at high
risk of developing diabetes.

12. Diabetes Care
October 2009; vol. 32: no.10: 1924-1929
Statin Therapy and Risk of Developing
Type 2 Diabetes: A Meta-Analysis
Swapnil N. Rajpathak, Dharam J. Kumbhani, Jill Crandall,
Nir Barzilai, Michael Alderman, Paul M. Ridker.
RESULTS
In the meta-analysis of the hypothesis-testing trials,
we observed a small increase in diabetes risk
(RR 1.13 [95% CI 1.03–1.23])

13. Meta-analysis of clinical trials evaluating the effects of statins on diabetes risk

14. June 22; 2011, Vol 305, No. 2
Risk of Incident Diabetes With Intensive-Dose
Compared With Moderate-Dose Statin Therapy
A Meta-analysis
David Preiss, Sreenivasa Rao Kondapally Seshasai,
Paul Welsh, Sabina A. Murphy, Jennifer E. David D.
Waters, David A. DeMicco, Philip Barter, Christopher P.
Cannon, Marc S. Sabatine, Eugene Braunwald, John J.
P. Kastelein, James A. de Lemos, Michael A. Blazing,
Terje R. Pedersen,Matti J. Tikkanen, Naveed Sattar,
Kausik K. Ray.

15. INTERPRETATION:
 Statin therapy is associated with a slightly
increased risk of development of diabetes, but
the risk is low both in absolute terms and when
compared with the reduction in coronary events.
 Clinical practice in patients with moderate or
high cardiovascular risk or existing
cardiovascular disease should not change.

16. Results



In 5 statin trials with 32.752 participants without diabetes at
baseline, 2749 developed diabetes (1449 assigned intensive-dose
therapy, 1300 assigned moderate-dose therapy, representing 2.0
additional cases in the intensive-dose group per 1000 patientyears) and 6684 experienced cardiovascular events (3134 and
3550, respectively, representing 6.5 fewer cases in the intensivedose group per 1000 patient-years) over a weighted mean (SD)
follow-up of 4.9 (1.9) years.
Odds ratios were 1.12 (95% confidence interval [CI], 1.041.22; I2 = 0%) for new-onset diabetes and 0.84 (95% CI, 0.750.94; I2 = 74%) for cardiovascular events for participants receiving
intensive therapy compared with moderate-dose therapy.
As compared with moderate-dose statin therapy, the number
needed to harm per year for intensive-dose statin therapy was 498
for new-onset diabetes while the number needed to treat per year
for intensive-dose statin therapy was 155 for cardiovascular events.
Conclusion: In a pooled analysis of data from 5 statin trials, intensivedose statin therapy was associated with an increased risk of new-onset
diabetes compared with moderate-dose statin therapy.

17. From: Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy: A Metaanalysis
JAMA. 2011;305(24):2556-2564. doi:10.1001/jama.2011.860
Figure Legend:
Data marker size indicates relative weight of the studies; OR, odds ratio; and CI, confidence interval.
Date of download: 9/23/2012
Copyright © 2012 American Medical
Association. All rights reserved.

18. From: Risk of Incident Diabetes With Intensive-Dose Compared With Moderate-Dose Statin Therapy: A Metaanalysis
JAMA. 2011;305(24):2556-2564. doi:10.1001/jama.2011.860
Figure Legend:
Data were available for age, high-density lipoprotein (HDL) cholesterol levels, and triglyceride concentrations in all trials; for body
mass index (BMI) in 4 trials; and for fasting plasma glucose levels in 3 trials. The medians of the variables are per-trial medians,
which are provided in the eTable. P values apply to heterogeneity between groups. Data marker si ze indicates relative weight of the
studies; OR, odds ratio; and CI, confidence interval.
Date of download: 9/23/2012
Copyright © 2012 American Medical
Association. All rights reserved.

19. Statins and risk of incident diabetes:
a collaborative meta-analysis of
randomised statin trials
Sattar N et al.- Lancet 2010;27;375:735-742

20. 13 statin trials
91.140 participants, of whom 4278 (2226 assigned statins and 2052
assigned control treatment) developed diabetes during a mean of 4
years.
Statin therapy was associated with a 9% increased risk for incident
diabetes (odds ratio [OR] 1·09; 95% CI 1·02—1·17), with little
heterogeneity (I2=11%) between trials.
Meta-regression showed that risk of development of diabetes with
statins was highest in trials with older participants, but neither
baseline body-mass index nor change in LDL-cholesterol
concentrations accounted for residual variation in risk.
Treatment of 255 (95% CI 150—852) patients with statins for 4
years resulted in one extra case of diabetes.
Interpretation
Statin therapy is associated with a slightly increased risk of
development of diabetes, but the risk is low both in absolute terms
and when compared with the reduction in coronary events.
Clinical practice in patients with moderate or high
cardiovascular risk or existing cardiovascular disease should
not change.
Sattar N et al. Lancet 2010

21. Statin Use and Risk of Diabetes
Mellitus in Postmenopausal Women
Annie L. Culver, et al. - Arch Intern Med.
Published online January 9, 2012

22. Study links statins to higher diabetes in
older women
Culver AL, Ockene IS, Balasubramanian R
Statin use and risk of diabetes mellitus in
postmenopausal women in the Women's
Health Initiative.
Arch Intern Med 2012;

23. 
Results

This investigation included 153 840
women without DM and no missing
data at baseline. At baseline, 7.04%
reported taking statin medication.
There were 10 242 incident cases of
self-reported DM over 1 004 466
person-years of follow-up.


Statin use at baseline was associated
with an increased risk of DM (hazard
ratio [HR], 1.71; 95% CI, 1.61-1.83).

This association remained after
adjusting for other potential
confounders (multivariate-adjusted
HR, 1.48; 95% CI, 1.38-1.59) and was
observed for all types of statin
medications.

Conclusions
 Statin medication use in
postmenopausal women is
associated with an increased
risk for DM.
 This may be a medication
class effect.
 Further study by statin type
and dose may reveal varying
risk levels for new-onset DM in
this population.
Subset analyses evaluating the
association of self-reported DM with
longitudinal measures of statin use in
125 575 women confirmed these
findings.
Arch Intern Med. Published online January 9, 2012

24. Statins raise risk of Type 2 diabetes in older women
Post-menopausal women who take statins to ward off heart attacks are more
likely to develop Type 2 diabetes than those who do not, research indicates.
January 10, 2012
By Melissa Healy, Los Angeles Times

26. Diabetes/statin link probed in EFFECT cohort
World Congress of Cardiology 2012
,,The message for the public is that statins have
documented benefits over many years. The risk of
developing diabetes with a statin vs placebo is probably
there, but when we talk about dose relationships, we can't
find any evidence of a difference between doses,"
Dr Altayyeb Yousef
(Institute for Clinical Evaluative Sciences, Toronto)

27. END POINTS
 deaths, deaths or ACS, or new-onset diabetes in
the EFFECT study cohort—all patients who had
been hospitalized for acute MI.
CONCLUSIONS
 Comparing results among 2870 matched
patients, they found no significant differences in
any of those three end points out to five years.
 At each year out to five years, the risk of
diabetes was actually lower, numerically, among
the intensive-statin group as compared with the
moderate-dose group, although differences were
not statistically significant.

28. Rautio N, Jokelainen J, Oksa H, et al.
BMJ 2012
Do statins interfere with lifestyle intervention
in the prevention of diabetes in primary
healthcare? One-year follow-up of the
FIN-D2D project

29. 
This is the first study examining the association of lifestyle
intervention on the risk of type 2 diabetes according to the use of
statins. This question is of utmost clinical importance, since we now
know that type 2 diabetes is preventable by lifestyle changes.

Fasting glucose increased by 0.08 mmol/L in statin users but
remained unchanged in nonusers. This was a significant difference
and remained so after adjustment for age, sex, baseline fasting
glucose, presence of CVD, use of antihypertensive and/or CAD
medication, weight, and one-year weight change.

An increase in fasting glucose in statin users suggests deterioration
in insulin secretion capacity, but added that two-hour glucose
values, which reflect insulin sensitivity, were similarly decreased in
statin users and nonusers.

30. 
"The message for clinicians is that patients who
have multiple components of the metabolic
syndrome need to try to further improve their
lifestyle habits to combat the possible rise in
glucose when a statin is begun. This paper
suggests that statins may have unfavorable
effects on glucose metabolism in certain people,
so compliance with lifestyle improvements will
be very important. We look forward to more
prospective studies on this topic."
Dr Nina Rautio -BMJ ; September 13, 2012

31. Statins, Risk of Diabetes, and
Implications on Outcomes in the
General Population
Kang-Ling Wang, et al.
J Am Coll Cardiol. 2012;60(14):1231-1238

32. Objectives
This study aimed to evaluate the
association of statin exposure and incident
diabetes, and subsequent outcomes in the
general population.
Kang-Ling Wang, et al. - J Am Coll Cardiol. 2012;60(14):1231-1238.

33. Results
Over a median of 7.2 years, annual rates of
diabetes were significantly higher in statin
users
(2.4% vs. 2.1%; p < 0.001)
MACE
HR: 0.82; CI 0.68-0.98 for myocardial infarction
HR: 0.94; CI 0.86-1.03 for ischemic stroke
HR: 0.91; CI:0.84-0.99 for MACE
In-hospital mortality
HR: 0.61; CI:0.55-0.67
Kang-Ling Wang, et al. - J Am Coll Cardiol. 2012;60(14):1231-1238.

34. The risk–benefit analyses



Statin treatment was favorable in high-risk and
secondary prevention populations.
Among diabetic patients, prior statin use was
associated with fewer MACE
In-hospital deaths were similar in statin-related
diabetes among high-risk and secondary
prevention subjects compared with nondiabetic
controls.
Conclusions
Risk of diabetes was increased after statins,
but outcomes were favorable.
Kang-Ling Wang, et al. - J Am Coll Cardiol. 2012;60(14):1231-1238

35. Kaplan-Meier Curves for Outcomes
Among Statin and Control Groups
(A) Cumulative incidences for newly developed
diabetes in the statin and control groups
were 22.7% and 20.8%, respectively.
(B) Cumulative incidences for major adverse
cardiovascular (CV) events (the composite
of myocardial infarction [MI] and ischemic
stroke) in the statin and control groups
were 11.6% and 12.6%,
(C) Cumulative incidences for in-hospital death
from all causes in the statin and control
groups were 8.8% and 13.8%.
Kang-Ling Wang, et al. - J Am Coll Cardiol. 2012;60(14):1231-1238.

36. J Am Coll Cardiol. 2011;57(14):1535-1545
Predictors of New-Onset Diabetes in
Patients Treated with Atorvastatin
Results From 3 Large Randomized Clinical Trials
David D. Waters, Jennifer E. Ho, David A.
DeMicco, Andrei Breazna,Benoit J.
Arsenault, Chuan-Chuan Wun, John J.
Kastelein, Helen Colhoun, Philip Barter

37. Predictors of New-Onset Diabetes
in Patients Treated With
Atorvastatin: Results From 3
Large Randomized Clinical Trials
J Am Coll Cardiol. 2011;57(14):1535-1545

38. Incident Diabetes According to
Number of Risk Factors
Incident diabetes in (A) the TNT trial, (B) the
IDEAL trial, and (C) the SPARCL trial
according to number of risk factors and
treatment group.
Atorva. = atorvastatin; ATV10 = atorvastatin 10
mg; ATV80 = atorvastatin 80 mg; Simva =
simvastatin;
J Am Coll Cardiol 2011;57(14):1535-1545

39. Conclusions
High-dose atorvastatin treatment
(80mg/day) compared with placebo in the
SPARCL trial is associated with a slightly
increased risk of new-onset T2DM.
Baseline fasting glucose level and
features of the metabolic syndrome are
predictive of new-onset T2DM across the
3 trials.
Waters DD et al. J Am Coll Cardiol. 2011;57(14):1535-1545

40. How effective are statins for
people with diabetes?

41. Most people with diabetes
'have poor cholesterol control'

Almost three-fifths of people
with diabetes do not meet their
cholesterol targets

An analysis by Diabetes UK found that
more than nine out of ten (91.6 per
cent) people with diabetes in England
now receive an annual check.

Yet almost 60 per cent of patients are
still not meeting their targets, the
research revealed.

43. How effective are statins for people with diabetes?
Collaborative Atorvastatin Diabetes
Study (CARDS)
This study involved nearly 3000 people
with Type 2 diabetes aged 40-75.
It looked at the benefits of taking a 10mg
dose of atorvastatin daily.
None of the participants had heart disease
at the start of the trial, but they did
have an extra risk factor for developing
it, such as smoking, high blood
pressure, diabetic retinopathy or
protein in the urine indicating diabetic
kidney disease.
For those taking the statin, the risk of heart
attack reduced by 37 per cent and
stroke by 48 per cent.
These benefits were seen regardless of
age, sex or whether the cholesterol
level was high or low.
The trial's success meant it was halted two
years early.

The Heart Protection Study (HPS)
The HPS study involved nearly 6000
people with diabetes aged 40-80.
It looked at the benefits of taking a 40mg
dose of simvastatin each day. Just
under half of the participants showed
signs of cardiovascular disease, while
half did not.
It found this routine use of statins cut the
number of heart attacks and strokes in
both groups by a third.


45. CONCLUSI
ONS

46. High-Dose Statins May Increase
Diabetes Risk
but,
Experts Say Most Heart Disease
Patients Are Better Off Taking a Statin,
Despite Increased Diabetes Risk