Statins are a class of drugs that inhibit the HMG Co-A reductase enzyme and subsequently reduce the cholesterol levels. HMG Co-A reductase enzyme is involved in the cholesterol synthesis in the liver and accounts for 70% of the production of total body cholesterol. High cholesterol levels attribute to cardiovascular disease in high-risk individuals. Statins have been found to reduce CVD endpoints in the initial stages of the disease (secondary prevention) but evidence is still weak to support statin therapy in those without CVD but with high cholesterol levels (primary prevention). Statins are also associated with certain adverse effects like muscle pain, incident diabetes and elevated liver enzymes and occasionally muscle damage; although very rare. In this review I shall explore one of these adverse effects of statin therapy particularly the link between statins and incident diabetes in the following report and try to shed some light into this controversial topic.
There is an increased risk of incident diabetes with statin use, which may be limited to those with diabetes risk factors.
These patients may benefit additionally from diabetes screening when on statin therapy.
In an analysis of one of the initial studies suggesting that statins are linked to increased risk of diabetes, the cardiovascular event rate reduction with statins outweighed the risk of incident diabetes even for patients at highest risk for diabetes .
The absolute risk increase was small (over 5 years of follow-up, 1.2% of participants on placebo developed diabetes and 1.5% on rosuvastatin) .
A meta-analysis of 13 randomized statin trials with 91,140 participants showed an odds ratio of 1.09 for a new diagnosis of diabetes, so that (on average) treatment of 255 patients with statins for 4 years resulted in one additional cause of diabetes, while simultaneously preventing 5.4 vascular events among 255 patients [3-4].
The relative risk-benefit ratio favoring statins is further supported by meta-analysis of individual data of over
170,000 persons from 27 randomized trials. This demonstrated that individuals at low risk of vascular disease, including those undergoing primary prevention, received benefits from statins that included reductions in major vascular events and vascular death without increase in incidence of cancer or deaths from another causes [5-6].
In this review I shall explore one of these adverse effects of statin therapy particularly the link between statins and incident diabetes in the following report and try to shed some light into this controversial topic.
Several statin preparations are available in the market like atorvastatin, rosuvastatin, fluvastatin, lovastatin, pravastatin, and simvastatin. All of these agents are equally effective at reducing cholesterol and vary only in their adverse effects with simvastatin and pravastatin exhibiting a slight superiority . The various statins also differ in their pharmacokinetics and dosing and are outlined in the tables below (Table 1 & 2) [7-8].
Statins competitively inhibit the HMG CoA reductase enzyme
which is involved in the biosynthesis of cholesterol. They are
molecularly similar to the enzyme and inhibit the conversion
from HMG CoA to mevalonate which further leads to inhibition
of cholesterol synthesis and ultimately cholesterol reduction via
several pathways. The following figure demonstrate how statins
affect cholesterol biosynthesis (Figure 1) . Statin therapy is
initiated after failure of lifestyle modifications by determining risk
category (Table 3) .
Diabetes is associated with a two to four-fold increased risk
of CVD compared to non-diabetics and intensive management
of all CVD risk factors, including dyslipidemia, is of paramount
importance in diabetics . Additionally, the beneficial effects
of LDL-C lowering with statins apply to people with and without
diabetes . Several trials have demonstrated the efficacy of
statins for the primary and secondary prevention of CVD in
diabetic individuals with the latter showing significant reductions
in CVD associated mortality and morbidity.
i. HPS Study : In the diabetes subgroup, 40mg
Simvastatin reduced CV events and stroke by 27% and 25%
respectively compared to placebo.
ii. CARDS Study  (10 mg Atorvastatin): Statin therapy
should be advocated for all patients with T2DM and other risk
factors irrespective of their LDL levels.
iii. CTT Collaborators : Diabetics had a 9% reduction in
all-cause mortality and 21% reduction in major vascular events
per mmol/L LDL-C reduction.
iv. ASPEN  (10 mg Atorvastatin): LDL-C was reduced
by 29% with Atorvastatin compared to placebo but the primary
endpoints of CVD were not significantly reduced. This poor
showing was due to the study design and protocol changes.
Atorvastatin): Primary end point of CVD was reduced by 16%
and CRP was also reduced which had positive benefit in CV event
reduction irrespective of decreased LDL .
ii. TNT Study  (10 mg vs. 80 mg Atorvastatin):
Significant 25% reduction in major cardiovascular events in the
high dose group with LDL lowering to 2mmol/l compared to
2.5mmol/l in the low dose group.
iii. A to Z trial  (20 mg Simvastatin titrated to 80 mg):
A reduction of 1.6mmol/l in the intensive group was seen with
reduction in primary outcome (CVD, nonfatal MI, ACS and stroke)
which, however, was not statistically significant.
iv. IDEAL trial  (Simvastatin 20 mg vs. Atorvastatin 80
mg): No significant reduction in major cardiovascular events but
reduction in nonfatal AMI, coronary revascularization, and PVD.
Recent meta-analyses point to a relative increase in diabetes
with prolonged statin use with this increased risk being attributed
to the statin dose [22-24]. US FDA issued a warning in 2012
linking statins with increased risk of new onset DM and worsening
glycaemic status in pre-existing diabetic patients. Several trials
have investigated the incidence of diabetes with statin therapy
and they are outlined below:
1. WOSCOPS  study (Pravastatin 40 mg): 30%
decreased incidence of diabetes with pravastatin therapy as
compared to placebo.
2. JUPITER  study (Rosuvastatin 20 mg): Associated
with significant reductions in the incidence of major coronary
events. There was however a significant increase in the rate of
physician-reported diabetes (26%) and an increase in median
3. PROSPER  study (Pravastatin 40 mg): Significant
LDL-C reduction by 34% but incidentally a 32% higher incidence
4. Meta-analysis by Rajpathak et al : studies were
carried out to analyze the outcomes of the WOSCOPS, ASCOT-LLA,
JUPITER, HPS, LIPID study and the CORONA study and showed
an average 13% higher incidence of diabetes.
5. Meta-analysis by Preiss and Waters: high dose statins
resulted in increased incidence of diabetes [24,28].
Statins differ in their lipophilic (atorvastatin, lovastatin, and
simvastatin) as well as hydrophilic properties (pravastatin and
rosuvastatin) and the results of the CORALL study showed a
significant increase in HbA1C with high dose rosuvastatin and
• There is no clear-cut cause-effect relationship, but
postulates include decreased insulin sensitivity with increasing
statin doses and decreased adiponectin with loss of antiproliferative
and antiangiogenic properties.
• Animal studies show decreased GLUT4 and increased
GLUT1 expression with atorvastatin with defective insulin
signaling and glucose transport defects in the adipocyte leading
to insulin resistance.
• Abnormal regulation of cholesterol within the cell
thereby impairing β cell function.
The results of these studies raised questions about the study
design (associations rather than causation), more importantly,
the fact that statins could well identify the patient already at
risk of developing diabetes and concluded that the benefit from
statin therapy in reducing CV events far outweighs the minor risk
of incident diabetes and LDL-C reduction with statins lowered
cardiovascular risk even in low-risk patients. However, caution
should be exercised in the low-risk primary prevention groups
without significant elevations in LDL-C, especially the elderly.
Statin therapy is advocated as a primary prevention of CVD
for moderate to high-risk diabetic patients with dyslipidemia and
as a secondary prevention for those with/without risk factors
and the incidence of new-onset diabetes should not result in
dose reduction or withdrawal in these patients. There appears
to be only a slight increase in new-onset DM whereas the cardioprotective
effects of statins clearly outweigh its risks. It would be
reasonable to implement lifestyle changes like weight reduction,
aerobic exercises, and dietary modification to prevent diabetes
rather than to stop statins in moderate to high-risk patients like the
elderly and in those with insulin resistance, metabolic syndrome
and established CVD who are on therapy for the appropriate
I would like to thank my colleagues at the Chittagong Diabetic
General Hospital, Institute of Applied Health Sciences and Cox’s
Bazar Medical College for their assistance in the writing and
critically revising the manuscript.
S.R.C. and S.R.A were involved
in data collection and drafted the manuscript. R.H.C. conceived
the study. S.R.C and S.R.A. wrote the manuscript with input
from all authors. S.R.A., R.H.C. and S.B. critically revised the final
manuscript. All authors approved of the final manuscript for