RAMB Julho/Agosto 2015

ernardi

378

ssoc

ras

2015; 61(4):375-380

insulin sensitivity.

35,36

Reduction of insulin secretion caused

by statin has been reported in some

in vitro

studies,

but

other studies in this model showed no such decrease.

Data from large meta-analyzes assessing the risk of

developing diabetes with statins, either compared to pla-

cebo

or compared to a less intensive treatment,

sug-

gest a causal relationship. Biases that could act as a con-

founding factors in this analysis are few. One suggestion

was that the survival bias could explain the findings. An-

other explanation would be that patients included in large

studies with significant reduction of LDL can become

complacent, changing their lifestyles to less healthy hab-

its, gaining weight and developing diabetes. JUPITER data

show that the average weight of patients treated with ro-

suvastatin increased by 0.3kg as compared to those re-

ceiving placebo.

Nevertheless, a significant increase in

the risk of developing diabetes probably could not be ex-

plained by this slight weight gain.

In order to evaluate if the relationship between statins

and diabetes could be directly correlated with the inhibi-

tion of HMGCoAR, the main therapeutic target of statins,

Swerdlow et al.

used the principle of Mendelian ran-

domization and examined the effect of two single nucle-

otide polymorphisms (SNPs) in the gene of HMGCoAR

on body weight and risk of type 2 diabetes. The results

showed that, similarly to statins in clinical trials, the

HMGCoAR variants that were assessed had an associa-

tion with higher body weight and risk of type 2 diabetes.

This implies, at least partially, that HMGCoAR inhibi-

tion is a causative factor of metabolic effects observed.

However, although the increase in body weight can deter-

mine a worsening of insulin resistance and increased risk

of type 2 diabetes, the magnitude of weight gain observed

both in clinical trials with statins and in genetic studies

seems insufficient to fully justify the risk of diabetes. For

example, intensive treatment with statin was not associ-

ated with a stronger effect on body weight than mild or

moderate doses of statin, despite the higher risk of dia-

betes associated with intensive care. Thus, it is possible

that there are also other mechanisms involved in diabe-

to-genicity of statins, including modulation of HMG-

CoAR at other sites, such as skeletal muscle, and off-tar-

get effects of statins. It seems plausible, therefore, that

one or more specific molecular mechanisms exist, al-

though other possibilities such as changes in body com-

position need to be considered. The possibility of bias, es-

pecially in the context of clinical trials, should be

considered: patients treated with statins may experience

more side effects, leading them to seek medical attention

with a greater chance of being diagnosed for diabetes.

There are numerous gaps that need to be answered

in addition to any specific mechanism. A particularly im-

portant issue is that of macrovascular and microvascular

complications of statin-induced diabetes. The increased

risk of diabetic complications is described in the study of

Mansi et al., who conducted a retrospective cohort study

among users of an American health provider between Oc-

tober 2003 and March 2012. 25,970 patients identified as

healthy adults (3,982 treated with statins and 21,988 who

did not use the drug) were selected. Of these, 3,351 users

of statins and 3,351 nonusers were matched according to

42 baseline characteristics, which generated a propensity

score. Thus, statin users had higher chances of new cas-

es of diabetes (OR 1.87; CI95% 1.67-2.01) and diabetic

complications (OR 2.50; CI95% 1.88-3.32).

iabetogenicity

statins

cardiovascu

lar

risk

reduction

able

Despite the diabetogenic effect, statins remain as an impor-

tant therapeutic pillar for cardiovascular risk reduction. Ac-

cording to current evidence, in the case of individuals with a

recommendation for the use of statins, especially those with

moderate or high risk, their cardiovascular benefit outweighs

the potential risk, even at high doses. In a meta-analysis by

Preiss et al., the authors found an additional case of diabetes

at every 498 patients treated for 1 year with intensive statin

therapy (

. moderate therapy), compared to 1 patient less

presenting a cardiovascular event at every 155 patients treat-

ed for 1 year.

These data suggest a wide advantage of us-

ing high-dose statin in patients for secondary prevention.

Individuals in primary prevention, analyzed by the JU-

PITER study, for example, also had significantly greater

cardiovascular benefits compared to the risks of using

statins. In analysis restricted to 486 participants who de-

veloped diabetes during follow-up (270 in the rosuvastatin

group

. 216 in the placebo group), the reduction of car-

diovascular risk associated with the use of statin was 37%

(hazard ratio [HR] 0.63, 95CI 0.25–1.60), consistent with

that observed in the study as a whole (0.56, 0.46–0.69). In

diabetic patients, the benefit of statins has also been dem-

onstrated. In the CTT’s meta-analysis, the relative reduc-

tion in cardiovascular risk of approximately 20% at each

reduction of LDLc of 39 mg/dL was consistent between

individuals with or without type 2 diabetes mellitus.

onclusion

A review of the current scientific literature suggests a con-

sistent association between statin use and increased risk

of developing type 2 diabetes. This association is stron-

ger in the elderly, with the use of higher doses of the drug,