Abstract

Objective To examine the risk of new onset diabetes among patients treated with different HMG-CoA reductase inhibitors (statins).

Design Population based cohort study with time to event analyses to estimate the relation between use of particular statins and incident diabetes. Hazard ratios were calculated to determine the effect of dose and type of statin on the risk of incident diabetes.

Setting Ontario, Canada.

Participants All patients aged 66 or older without diabetes who started treatment with statins from 1 August 1997 to 31 March 2010. The analysis was restricted to new users who had not been prescribed a statin in at least the preceding year. Patients with established diabetes before the start of treatment were excluded.

Interventions Treatment with statins.

Main outcome measure Incident diabetes.

Results Compared with pravastatin (the reference drug in all analyses), there was an increased risk of incident diabetes with atorvastatin (adjusted hazard ratio 1.22, 95% confidence interval 1.15 to 1.29), rosuvastatin (1.18, 1.10 to 1.26), and simvastatin (1.10, 1.04 to 1.17). There was no significantly increased risk among people who received fluvastatin (0.95, 0.81 to 1.11) or lovastatin (0.99, 0.86 to 1.14). The absolute risk for incident diabetes was about 31 and 34 events per 1000 person years for atorvastatin and rosuvastatin, respectively. There was a slightly lower absolute risk with simvastatin (26 outcomes per 1000 person years) compared with pravastatin (23 outcomes per 1000 person years). Our findings were consistent regardless of whether statins were used for primary or secondary prevention of cardiovascular disease. Although similar results were observed when statins were grouped by potency, the risk of incident diabetes associated with use of rosuvastatin became non-significant (adjusted hazard ratio 1.01, 0.94 to 1.09) when dose was taken into account.

Conclusions Compared with pravastatin, treatment with higher potency statins, especially atorvastatin and simvastatin, might be associated with an increased risk of new onset diabetes.

Discussion

In this population based study, we found that patients treated with atorvastatin, rosuvastatin, or simvastatin were at increased risk of new onset diabetes compared with those treated with pravastatin. No such risk was evident with fluvastatin or lovastatin. The risk associated with rosuvastatin could depend on dose and duration of treatment. The risk of incident diabetes was similar whether statins were being used for primary or secondary prevention.

Overall, we observed a 10-22% increased risk of diabetes for some statins that is consistent with findings from previously published meta-analyses of clinical trials. The increased risk with rosuvastatin significantly decreased after covariate adjustment and became non-significant once dose was taken into consideration. This could possibly represent greater use of rosuvastatin in patients with lower cardiovascular risk.³ In 2009, an analysis of five placebo controlled trials (n=57 593) found a 13% (relative risk 1.13, 95% confidence interval 1.03 to 1.23) increased incidence of diabetes in people taking statins compared with placebo over an average 3.9 years of follow-up,⁹ with a subsequent analysis of 13 placebo controlled trials (n=91 140) showing a 9% (odds ratio 1.09, 95% confidence interval 1.02 to 1.17) increased incidence of diabetes over four years of follow-up.¹⁰ More recently, two meta-analyses have suggested a dose dependent effect for patients receiving high dose atorvastatin or simvastatin treatment versus moderate dose treatment (odds ratio 1.12, 95% confidence interval 1.04 to 1.22) and when considering only atorvastatin trials.^11 12 Our results differ from those of the Women’s Health Initiative study, which showed a nearly 50% increase in new onset diabetes with statins compared with placebo (hazard ratio 1.48, 95% confidence interval 1.38 to 1.59), with no differential risk among low potency (fluvastatin, lovastatin, pravastatin) and high potency (simvastatin, atorvastatin) statins.¹⁴ Our findings, however, are consistent with the findings of Zaharan and colleagues in 2012, who found an increased risk with atorvastatin (hazard ratio 1.25, 1.21 to 1.28), rosuvastatin (1.42, 1.33 to 1.52), and simvastatin (1.14, 1.06 to 1.23).³⁰ Our population based assessment adds to the discussion of risk when doctors are considering starting statin treatment in a patient for primary versus secondary prevention.

Possible mechanisms

Several factors could explain the increased risk of new onset diabetes among patients receiving certain statins.^2 7 15 The increased production of plasma derived low density lipoprotein (LDL) cholesterol as a compensatory response to de novo cholesterol synthesis inhibition might result in direct inflammation and oxidation within the β cell. Consequently, the functional and structural integrity of β cells is compromized, impairing insulin secretion as a result of cellular apoptosis.¹⁵Additionally, metabolic receptor effects interfere with cellular glucose uptake, energy production, and insulin secretion.^2 7 15 16 Statins can also inhibit calcium mediated pancreatic insulin release and decrease expression of the β cell glucose transporters GLUT-2 and GLUT-4.¹⁵ Finally, statins are also known to interfere with the synthesis of ubiquinone (CoQ10), which could independently alter insulin secretion.^15 16 The degree to which statins are involved in these respective mechanisms of diabetes onset is variable and supports why some statins pose a higher risk than pravastatin.⁷ As shown in our dose and potency analyses, the risk could be greater for atorvastatin and simvastatin, regardless of the dose prescribed.

Limitations and strengths

Some limitations of our study merit emphasis. We could not identify and account for potentially important risk factors for diabetes such as weight, ethnicity, and family history. Newer statins might be preferentially used in patients at higher risk of diabetes, though the characteristics of patients in our study were highly similar across study groups. Secondly, data on blood lipids, hemoglobin A_1C concentration, or triglyceride concentrations were unavailable, and therefore we could not use these measures for risk stratification or diagnostic purposes. The ODD, however, has been shown to be both sensitive (86-90%) and specific (92-97%).¹⁹ Furthermore, we had no data on marketing or promotional efforts nor did we have data on physicians’ preferences for particular statins. Although the statin groups were well balanced with respect to a wide variety of demographic and clinical variables, we cannot exclude the possibility of residual confounding.

Our study also had several strengths including a large sample size, use of pravastatin as an active comparator reference group, and a population based design. Our findings suggest that older patients treated with certain statins are at increased risk for incident diabetes, regardless of dose or whether treatment is used for primary or secondary prevention. The risk seems to be greatest with atorvastatin, rosuvastatin, and simvastatin. After adjustment for dose, however, the risk did not seem to persist among rosuvastatin users. Clinicians should consider this risk when they are contemplating statin treatment for individual patients. Preferential use of pravastatin, and potentially fluvastatin or lovastatin, while recognizing the limited efficacy data and increased risk of drug interactions with these two agents, might be warranted. Pravastatin might have a preferential benefit among primary prevention patients at high risk of diabetes.

What is already known on this topic

• Given the widespread use of statins to manage hypercholesterolemia, small effects in their efficacy and safety profiles can have important population impact.
• Statins have previously been associated with an increased risk of incident diabetes, though there is controversy around whether this risk differs among drugs
• When compared with pravastatin, atorvastatin, rosuvastatin, and simvastatin are associated with a greater risk of new onset diabetes, regardless of their use for primary or secondary prevention of cardiovascular events
• The risk for rosuvastatin users might depend on the dose prescribed

What this study adds

Source: BMJ