Statins-induced Diabetes

between risks and benefits

Budi Susetyo Pikir

Department of Cardiology & Vascular Medicine
Dr. Soetomo Hospital / Airlangga University Hospital
Faculty of Medicine / Airlangga University
Surabaya
Reported Adverse Effects of Statins

Muscle-related symptoms
Elevated hepato-cellular enzymes
Cancer
New diabetes
Hemorrhagic stroke
Fatigue
Neuro-psychiatric effects and insomnia
Proteinuria / hematuria
Erectile dysfunction
Alopecia
 STATIN-INDUCED DIABETES

1. Clinical Evidence :
a. Major Statin Trial
b. Meta-analysis
2. Predictor of New Onset Diabetes (NOD)
3. Low-Dose vs High-Dose Statin Therapy
4. Types of Statin
5. Mechanism o9f Diabetogenic Effect of
Statin
 STATIN-INDUCED DIABETES

1. Clinical Evidence :
a. Major Statin Trial
b. Meta-analysis
2. Predictor of New Onset Diabetes (NOD)
3. Low-Dose vs High-Dose Statin Therapy
4. Types of Statin
5. Mechanism o9f Diabetogenic Effect of
Statin
 Statins and New-Onset Diabetes
Proportion of patients with
new-onset diabetes (%)
Study Statins Placebo RR, statin vs 95% CI
placebo
WOSCOPS (N=5974) 1.9% 2.8% 0.69 0.49-0.96
HPS (N=14,543) 4.6% 4.0% 1.14 0.98-1.33
ASCOT (N=7773) 3.9% 3.5% 1.14 0.90-1.43
LIPID (N=7937) 4.3% 4.6% 0.95 0.77-1.16
CORONA (N=3534) 5.6% 5.0% 1.13 0.86-1.49
JUPITER (N=17,802) 3.0% 2.4% 1.25 1.05-1.49
Combined all above (N=57,593) 3.8% 3.5% 1.06 0.93-1.22 (P=0.38)
Combined all above except 4.0% 3.5% 1.13 1.03-1.23 (P=0.008)
WOSCOPS (N=51,619)

Absolute risk of developing DM 0.3-0.5% Risk factors for Statin associated DM

Note Obesity
Patient reported diabetes IFG
No formal testing for diabetes Elevated TG / HDL

Sattar N et al. Lancet 2010; 375:735-42

 Prospective meta-analysis: 90,056 participants in 14
randomized statin trials

For each 1 mmol/L LDL-C lowering

12% reduction in all-cause mortality (P<0.0001)
19% reduction in coronary mortality (P<0.0001)
23% reduction in MI and coronary death (P<0.0001)
24% reduction in revascularizations (P<0.0001)
17% reduction in fatal or non-fatal stroke (P<0.0001)
21% reduction in any major vascular event (P<0.0001)
No increase in non-vascular mortality or cancers

Adapted from Baigent C et al. Cholesterol Treatment Trialists (CTT) Collaborators. Lancet 2005;
366:1267-78
 Effect of Statins on CV Event Rates
Related to 1 mmol/l LDL Reduction

More Less Relative risk per 1 mmol/L

statin statin (39 mg/dl) reduction in LDL-C
(95% CI)
A. More statin vs less statin (5 trials: 0.51 mmol/L LDL difference)
Any major coronary event 1725 (1.9) 1973
0.74(2.2)
(0.65-0.85)
Any coronary revascularization 2250 (2.6) 2741
0.66(3.2)
(0.60-0.73)
Any stroke 572 (0.6) 663
0.74(0.7)
(0.59-0.92)
5 trials: any major vascular event 3837 (4.5) 4416
0.72(5.3)
(0.66-0.78)

0.50 0.75 1.00 1.25 1.50

More statin better Less statin better
Statin Control
B. Statin vs control (21 trials: 1.07 mmol/L LDL difference)
Any major coronary event 3380 (1.3) 4539
0.76(1.7)
(0.73-0.79)
Any coronary revascularization 3103 (1.2) 4066
0.76(1.6)
(0.73-0.80)
Any stroke 1730 (0.7) 2017
0.85(0.8)
(0.80-0.90)
21 trials: any major vascular event 7136 (2.8) 8934
0.79(3.6)
(0.77-0.81)

0.50 0.75 1.00 1.25 1.50

Statin better Control better
CCT Trialists. Lancet 2010;376:1670
 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
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.
 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 1.031.23])
Meta-analysis of clinical trials evaluating the effects of
statins on diabetes risk
 Statins and risk of incident diabetes:
a collaborative meta-analysis of randomised
statin trials

Sattar N et al.- Lancet 2010;27;375:735-742

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] 109; 95% CI 102117), 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 150852) 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

 Statin Use and Risk of Diabetes Mellitus in
Postmenopausal Women

Annie L. Culver, et al. - Arch Intern Med.

Published online January 9, 2012
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;
 Results
This investigation included 153 840
women without DM and no missing data
at baseline. At baseline, 7.04% reported
taking statin medication. Conclusions
There were 10 242 incident cases of self- Statin medication use in
reported DM over 1 004 466 person-years postmenopausal women is
of follow-up.
associated with an increased risk
Statin use at baseline was associated with
for DM.
an increased risk of DM (hazard ratio [HR], This may be a medication class
1.71; 95% CI, 1.61-1.83). effect.
Further study by statin type and
This association remained after adjusting

for other potential confounders dose may reveal varying risk

(multivariate-adjusted HR, 1.48; 95% CI, levels for new-onset DM in this
1.38-1.59) and was observed for all types population.
of statin medications.

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

END POINTS
deaths, deaths or ACS, or new-onset diabetes in the
EFFECT study cohortall 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.
 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
 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.
 "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

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
 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.

 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.

 The riskbenefit 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
 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.

Statins and New-Onset Diabetes

Treatment of 255 patients with statins results

in 1 additional case of diabetes over 4 years

Statin treatment prevented of 5.4 vascular events

in these 255 patients

Benefit of statin treatment exceeds risk

Monitor fasting glucose and A1C
 STATIN-INDUCED DIABETES

1. Clinical Evidence :
a. Major Statin Trial
b. Meta-analysis
2. Predictor of New Onset Diabetes (NOD)
3. Low-Dose vs High-Dose Statin Therapy
4. Types of Statin
5. Mechanism o9f Diabetogenic Effect of
Statin
PREDICTORS OF DIABETES
1. IFG
2. Metabolic Syndrome
3. Elevated Hba1c
4. Elevated Triglyseride serum
5. Elevated BMI (overweight and
obese).
6. Hypertension
 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
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

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

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

 STATIN-INDUCED DIABETES
1. Clinical Evidence :
a. Major Statin Trial
b. Meta-analysis
2. Predictor of New Onset Diabetes
3. Low-Dose vs High-Dose Statin Therapy
4. Types of Statin
5. Mechanism o9f Diabetogenic Effect of
Statin
 Benefits of More vs Less Intensive
Statin Therapy: (5 RCTs, N=39,612)

Intensive therapy statin therapy resulted in a

further reduction of LDL-C of 0.51mmol/L

After 1 year:
15% reduction in major vascular events

13% reduction of coronary death or non-fatal MI

16% reduction in ischaemic stroke

CTT Lancet 2010; 376: 1670-

81
 Statins and New-Onset Diabetes In Context of Reduction of CV Events:
5 Trials Comparing Intensive- to Moderate-Dose Statin Therapy
Cases/Total (%)
Incident Diabetes
Intensive dose Moderate dose OR (95% CI)
PROVE-IT - TIMI 22, 2004 101/1707 (5.9) 99/1688 (5.9) 1.01 (0.76-1.34)
A to Z, 2004 65/1768 (3.7) 47/1736 (2.7) 1.37 (0.94-2.01)
TNT, 2005 418/3798 (11.0) 358/3797 (9.4) 1.19 (1.02-1.38)
IDEAL, 2005 240/3737 (6.4) 209/3724 (5.6) 1.15 (0.95-1.40)
SEARCH, 2010 625/5398 (11.6) 587/5399 (10.9) 1.07 (0.95-1.21)

Pooled odds ratio 1449/16,408 (8.8) 1300/16,344 (8.0) 1.12 (1.04-1.22)

0.5 1.0 2.0
Incident CVD
PROVE-IT - TIMI 22, 2004 315/1707 (18.4) 355/1688 (21.0) 0.85 (0.72-1.01)
A to Z, 2004 212/1768 (12.0) 234/1736 (13.5) 0.87 (0.72-1.07)
TNT, 2005 647/3798 (17.0) 830/3797 (21.9) 0.73 (0.65-0.82)
IDEAL, 2005 776/3737 (20.8) 917/3724 (24.6) 0.80 (0.72-0.89)
SEARCH, 2010 1184/5398 (21.9) 1214/5399 (22.5) 0.97 (0.88-1.06)

Pooled odds ratio 3134/16,408 (19.1) 3550/16,344 (21.7) 0.84 (0.75-0.94)

0.5 1.0 2.0
NTT/yr 155 for CV events Odds ratio (95% CI)
NNH/yr 498 for new-onset diabetes

Preiss D et al. JAMA 2011; 305:2556-64

 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.
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.
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 patient-years) and 6684 experienced
cardiovascular events (3134 and 3550, respectively, representing 6.5
fewer cases in the intensive-dose 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], 1.04-1.22; I2 = 0%)
for new-onset diabetes and 0.84 (95% CI, 0.75-0.94; 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, intensive-dose statin therapy was associated with
an increased risk of new-onset diabetes compared with
moderate-dose statin therapy.
 STATIN-INDUCED DIABETES

1. Clinical Evidence :
a. Major Statin Trial
b. Meta-analysis
2. Predictor of New Onset Diabetes (NOD)
3. Low-Dose vs High-Dose Statin Therapy
4. Types of Statin
5. Mechanism o9f Diabetogenic Effect of
Statin
 TYPE OF STATIN
Primary & Secondary Prevention of CVD
Pravastatin vs Simvastatin, Atorvastatin & Rosuvastatin
(increased risk of incident of Diabetes).
Pravastatin vs Fluvastatin & Lovastatin (no significant risk of
incident of Diabetes)
Pitavasta n 4 & 20 mg 40 % dose of Atorvasta n :
15-25 % increased on HDL-C
Favourable effect on glucose control (decrease HOMA score
& Hba1c)
no large trials have been performed
 STATIN-INDUCED DIABETES

1. Clinical Evidence :
a. Major Statin Trial
b. Meta-analysis
2. Predictor of New Onset Diabetes (NOD)
3. Low-Dose vs High-Dose Statin Therapy
4. Types of Statin
5. Mechanism of Diabetogenic Effect of
Statin
ANTIOXIDANTS & REDOX SIGNALING Volume 20, Number 8, 2014. Differential Metabolic Actions of Specific Statins:
Clinical and Therapeutic Considerations
 Possible Mechanism of
Diabetogenic Effect of STATIN

Chan DC & JPang J & Gerald F. Watts P. Pathogenesis and Management of the Diabetogenic
Effect of Statins: a Role for Adiponectin and Coenzyme Q10?Curr Atheroscler Rep (2015) 17:472
Pathophysiology
 SUMMARY
1. Statin ---> minor increase on Incident of New
Onset Diabetes (0.3 0. %)
2. Incident increase with higher dose of Statin
3. Predictors of Diabetes were IFG, Metabolic
Syndrome, elevated Hba1c, elevated TG,
elevated BMI. Hypertension
4. Although New onset of diabetes is one of the
side-effect of statin, but benefit of the statin
in CVD is bigger than this effect
THANK YOU
 High-Dose Statins May Increase
Diabetes Risk

but,

Experts Say Most Heart Disease Patients Are

Better Off Taking a Statin, Despite Increased
Diabetes Risk
 Non-Statin Lipid Lowering Strategies
Ezetimibe Fibrates
Lowers LDL 15-20% TG LDL little change
Well tolerated ? Benefit when HDL low
May be added to
low dose statin
Niacin
Bile acid sequestrants Flushing/pruritus may limit
Lowers LDL 15%
May prevent diabetes tolerance
Colesevalam better Lowers LDL 20%
tolerated TG 40%, HDL 30%

Ezetimibe + Bile acid sequestrant

40-45% LDL reduction
 Future Non-Statin Strategies
to Reduce LDL Cholesterol
CETP inhibitor
Torcetrapib (increased mortality) and Dalcetrapib (no benefit)
Anacetrapib results awaited ( HDL 138%, LDL 40%)
Evacetrapib Phase 2 study presented 2010

Mipomersen
Inhibits protein synthesis of apoB
Reduces LDL ~30%
Injected weekly
No outcomes trials

PCSK9 inhibitors
Reduce LDL 50-60 %,
Injected q 2 weeks
No outcomes trials
 Biochemical Effects of Statins
Acetate
Acetyl-CoA
Acetoacetyl-CoA
HMG-CoA Co-enzyme Q10
Statins Protein
Mevalonate prenylation
MVK
Mevalonate-5-P Geranylgeranyl-PP
Mevalonate-5-PP
Geranyl-PP Farnesyl-PP Squalene
Isopentyl-PP
Dolichols Squalene-2,3-epoxide
Sec-tRNA
N-linked glycosylation Lanosterol
7-Dehydrocholesterol *3
Lanosterol Cholestadien-3-ol
DHCR7
DHCR24
Cholesterol Desmosterol *2
How effective are statins for people
with diabetes?
 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.
 How effective are statins for people with diabetes?

Collaborative Atorvastatin Diabetes Study The Heart Protection Study (HPS)

(CARDS) The HPS study involved nearly 6000 people
This study involved nearly 3000 people with with diabetes aged 40-80.
Type 2 diabetes aged 40-75. It looked at the benefits of taking a 40mg dose
It looked at the benefits of taking a 10mg dose of simvastatin each day. Just under half of
of atorvastatin daily. the participants showed signs of
None of the participants had heart disease at cardiovascular disease, while half did not.
the start of the trial, but they did have an It found this routine use of statins cut the
extra risk factor for developing it, such as number of heart attacks and strokes in
smoking, high blood pressure, diabetic both groups by a third.
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.