Clinical Context

Statins are associated with significantly reducing the risk for cardiovascular events when used as either primary or secondary prevention. Moreover, statins are generally well tolerated, with myalgias and elevations in liver transaminase levels limiting treatment for a minority of patients.

The association of statins with the risk for incident diabetes is less well understood, but a previous meta-analysis of 13 clinical trials of statins featuring a total of 91,140 patients suggests that the risk for diabetes associated with these medications is real. This research by Sattar and colleagues, which was published in the February 27, 2010, issue of the Lancet, found that the use of statins was associated with a 9% increased risk for diabetes, with little heterogeneity among the trials. The risk for diabetes associated with statins was particularly profound for older adults, although body mass index and the efficacy of the statin on lipid values did not alter this result. Nonetheless, the authors of the study calculate a high number needed to harm in terms of the risk for diabetes with statin therapy. A total of 255 patients receiving statins for 4 years would produce 1 additional case of diabetes.

The diagnosis of diabetes in this previous research was based on fasting plasma glucose levels or clinician diagnosis, but other studies linking statins with the risk for diabetes have used even less stringent criteria to identify diabetes. The current study by Cederberg and colleagues uses data from a cohort of men who underwent glucose tolerance testing to further explore the risk for incident diabetes associated with statin use.

Study Synopsis and Perspective

Statin therapy appears to increase the risk for type 2 diabetes by 46%, even after adjustment for confounding factors, a large new population-based study concludes.

This suggests a higher risk for diabetes with statins in the general population than has previously been reported, which has been in the region of a 10% to 22% increased risk, report the researchers, led by Henna Cederberg, MD, PhD, from the University of Eastern Finland and Kuopio University Hospital, and colleagues, who published their study online March 4 and in the May issue of Diabetologia.

The majority of people in this new study were taking atorvastatin and simvastatin, and the risk for diabetes was dose dependent for these 2 agents, the researchers found.

Nevertheless, senior author Markku Laakso, MD, from the University of Eastern Finland and Kuopio University Hospital, told Medscape Medical News: "Even if statin treatment is increasing the risk of getting diabetes, statins are very effective in reducing cardiovascular risk.

"Therefore I wouldn't make a conclusion from my study that people should stop statin treatment, especially those patients who have a history of myocardial infarction or so on.

"But what I would say is that people who are at the higher risk, if they are obese, if they have diabetes in the family, etc, should try to lower their statin dose, if possible, because high-dose statin treatment increases the risk vs lower-dose statin treatment," he continued.

Asked to comment, Alvin C Powers, MD, from Vanderbilt University School of Medicine, Nashville, Tennessee, explained that there were limitations to the conclusions that could be drawn from this study.

Speaking as part of the Endocrine Society, he said: "The first thing is that this study did not examine the benefits of statin therapy, it examined only the risk of diabetes."

With every treatment, there are risks and benefits, and the benefits of statins have been clearly proven in certain situations. In those instances, "the benefit would outweigh the increased risk of diabetes for many people," Dr Powers told Medscape Medical News.

Statins Appear to Affect Insulin Secretion and Sensitivity

Dr Cederberg and colleagues explain that previous studies have suggested an increased risk for the development of diabetes, of varying levels, associated with statin use. However, in many of these, study populations have been selective, especially in statin trials, which have included participants at high risk for cardiovascular disease.

Hence, the risk for diabetes in clinical trials is likely to differ from that in the general population. And very often, in previous studies the diagnosis of diabetes has been based on self-reported diabetes or fasting glucose measurement, leading to an underestimation of the actual numbers of incident diabetes cases.

In this new study, the authors investigated the effects of statin treatment on blood glucose control and the risk for type 2 diabetes in 8749 nondiabetic men 45 to 73 years old in a 6-year follow-up of the population-based Metabolic Syndrome in Men trial, based in Kuopio, Finland.

The authors also investigated the mechanisms of statin-induced diabetes by evaluating changes in insulin resistance and insulin secretion.

Diabetes was diagnosed via an oral glucose tolerance test, glycated hemoglobin levels of 6.5% or higher (48 mmol/mol), or initiation of glucose-lowering medication. During the follow-up, 625 of the participants were diagnosed with diabetes. Indices derived from oral glucose tolerance tests were used to assess insulin sensitivity and secretion.

A total of 2412 individuals were taking statins. The drugs were associated with an increased risk for type 2 diabetes even after adjustment for age, body mass index, waist circumference, physical activity, smoking, alcohol intake, a family history of diabetes, and beta-blocker and diuretic treatment, at a hazard ratio (HR) of 1.46.

The risk was found to be dose dependent for simvastatin and atorvastatin, which were taken by 388 and 1409 participants, respectively. High-dose simvastatin was associated with an HR of 1.44 for diabetes vs 1.28 for low-dose therapy, whereas the HR for diabetes with high-dose atorvastatin was 1.37.

Statin therapy was also associated with a significant increase in 2-hour glucose (P = .001) and the glucose area under the curve at follow-up (P < .001), as well as a nominally significant increase in fasting plasma glucose levels (P = .037).

Furthermore, individuals taking statins had a 24% decrease in insulin sensitivity and a 12% reduction in insulin secretion compared with those not receiving the drugs. These increases were again dose dependent for atorvastatin and simvastatin.

Although pravastatin, fluvastatin, and lovastatin were found to be less diabetogenic than atorvastatin and simvastatin, the number of participants taking these agents was too small to reliably estimate their individual effects on the risk for diabetes, the research team notes.

Which Patients Should Take Statins?

Discussing the take-home message for prescribers seeking to balance the risk for diabetes with the benefits of statin therapy, Dr Laakso reiterated that individuals with a history of cardiovascular events and high low-density lipoprotein cholesterol levels "should definitely take statins."

However, he emphasized that the main aim of statins is to prevent a recurrent cardiovascular event, so individuals need to have had 1 event to start statin therapy.

"But in primary prevention, especially in women, who are at a lower risk of getting cardiovascular disease, maybe we should be more careful when we start statin treatment?" he ventured. "Statins are not meant to be a treatment for everybody."

Dr Powers observed that this new study does not provide any information about whether people who have diabetes and are receiving a statin should continue with the statin, "but there are clear benefits for statin therapy in people who have diabetes.

"People who have diabetes who are on a statin should continue with the statin...This increased risk of diabetes, to me, is not relevant to their reason for taking the statin," he commented.

And in diabetes patients who have heart disease and are taking a statin, "the risk/benefit ratio would clearly be in the direction of benefit," Dr Powers observed.

In individuals who do not have diabetes and who are taking a statin, for example, to reduce their risk for cardiovascular disease, "statin therapy has to be considered in the context of what's the benefit of the statin therapy in that group...especially in individuals who are genetically susceptible to type 2 diabetes or who have prediabetes," he continued.

"Those individuals will need to be monitored for the development of diabetes."

"People who are taking statins should keep taking statins, if there's an appropriate reason for them taking a statin. The risk/benefit ratio in most people is in favor of benefit; the risk is outweighed by that benefit," he concluded.

This work has been supported by the Academy of Finland, the Finnish Diabetes Research Foundation, the Finnish Cardiovascular Research Foundation, the Strategic Research Funding from the University of Eastern Finland, Kuopio, and a grant from Kuopio University Hospital. The authors have disclosed no relevant financial relationships.

Diabetologia. 2015;58:1109-1117. Abstract

Clinical Implications

• A previous meta-analysis of clinical trials by Sattar and colleagues found a 9% increased risk for incident diabetes among patients treated with statins, with a stronger risk among older adults. However, the number needed to harm with statin therapy was fairly high.
• The current study by Cederberg and colleagues suggests that statins can reduce insulin sensitivity and insulin secretion, and statin use was associated with a 46% higher adjusted risk for incident diabetes.

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