Alzheimer's Risk May Vary Among Statins

December 21, 2017

Contrary to expectations, a new study in almost half a million patients looking at differential effects of various statins on Alzheimer's disease risk has not shown a benefit for fungus-derived or lipophilic agents compared with synthetic and hydrophilic agents.

If anything, fungus-derived or lipophilic statins were associated with slightly higher risks for Alzheimer's disease compared with synthetic and hydrophilic agents, with a particular focus on simvastatin.

"Our results showed a slight variation in terms of risk between different types of statins," senior author, Paul Brassard, MD, McGill University, Montreal, Quebec, Canada, commented to Medscape Medical News. "Previous data suggest that fungus-derived and lipophilic statins may be better in terms of Alzheimer's risk, but we actually found these agents to be slightly worse. But after excluding patients who switched from one statin to another, these differences lessened."

"Our results suggest that there isn't a clear difference between individual types of statins," he said. "And in terms of clinical decision making when choosing a statin, the effect on the risk of Alzheimer's should not be a consideration."

The study was published online in Neurology on December 15.

Dr Brassard noted that Alzheimer's disease is not a single entity and that vascular ethology plays a role.

"It has been hypothesized that this may be modulated by statins, which are well known to reduce vascular disease," he said. "The literature on statins and Alzheimer's risk is mixed with some studies suggesting a slight benefit while others show no effect, but the data mainly come from observational studies and there are always methodological issues. In addition, some patients complain of memory issues when taking statins, but a meta-analysis of all studies looking at this was inconclusive.  And memory issues may be different from a clinical diagnosis of Alzheimer's disease. So we don't really know if these drugs have positive or negative effects on memory and Alzheimer's."

The current study did not address the overall effect of statins on Alzheimer's risk but rather focused on whether the risk varied among different types of statins.

The researchers explain that statins can be classified in various ways. One of these is fungus-derived (type 1), such as lovastatin, pravastatin, and simvastatin, vs synthetic (type 2), such as atorvastatin, fluvastatin, rosuvastatin, and pitavastatin.

Some experimental studies have suggested that the type 1 statins may have more neuroprotective potential compared with type 2 statins in that they show higher permeability through the blood–brain barrier and reduced cholesterol level in neurons and may prevent neurofibrillary degeneration.

Others have hypothesized that lipophilic statins have a better potential to cross the blood–brain barrier than do hydrophilic statins, resulting in a higher concentration in the brain tissue.

"We looked at whether different statins were associated with different effects on the risk of developing Alzheimer's disease in a large observational study using the UK Clinical Practice Research Datalink, a well-validated clinical database, and we adjusted for a variety of different factors," Dr Brassard said.

The researchers analyzed data on 465,085 patients aged 60 years or older who were newly prescribed a statin in 1994 and 2012 and who were followed until 2015. Statins were consecutively classified according to their type (fungus-derived or synthetic), lipophilicity, and potency.

During the 18-year study period, 7669 patients developed Alzheimer's disease, for an incidence rate of 2.65 per 1000 person-years.

The primary analysis showed that compared with synthetic statins, fungus-derived statins were associated with an increased risk for Alzheimer's disease (hazard ratio [HR], 1.09; 95% confidence interval [CI], 1.03 - 1.15). However, when patients with mixed exposure were assigned to a separate category (switchers), the difference in the risk for Alzheimer's disease between fungus-derived and synthetic statins was no longer significant.

Among individual statins, only simvastatin was associated with a higher risk for Alzheimer's disease compared with atorvastatin, while no such risk was evident for pravastatin, the only other fungus-derived statin in the study. However, the risk for simvastatin was not consistent and failed to reach significance in an analysis where statin exposure was lagged up to 3 years.

Lipophilic statins also were associated with a higher risk of Alzheimer's disease (HR, 1.18; 95% CI, 1.09 - 1.27) compared with hydrophilic statins, while statin potency did not modify the risk.

The researchers say that the slight increased risks observed with type 1 and lipophilic statins are unexpected findings with no underlying biological rationale to date. Despite the use of an active comparator group and adjustment with propensity scores, they may be partly explained by the presence of residual confounding.

But the authors conclude, "The modest variations in the risk of incident AD [Alzheimer's disease] observed between statin characteristics needs to be evaluated in future studies of their possible heterogeneous neuroprotective effect."

Is Simvastatin the Culprit?

In an accompanying editorial, Sevil Yasar, MD, Johns Hopkins School of Medicine, Baltimore, Maryland, and Rachel Whitmer, PhD, Kaiser Permanente and University of California San Francisco, point out that findings from observational studies are mixed regarding the effect of statins on Alzheimer's disease, although two meta-analyses of prospective studies showed a slight protective association. There is only one randomized clinical trial — the Heart Protection Study of simvastatin — which included dementia as an endpoint, and this showed no benefit on dementia prevention.

They further point out that in 2012, the US Food and Drug Administration issued a new warning for the labeling of statin drugs regarding potential adverse effects on cognition, but a later meta-analysis of 25 randomized trials found no effect of statins on cognitive function.

The editorialists point out that the findings in the current study of a slight increased risk with fungus-derived and lipophilic statins "are most likely explained by simvastatin, since it is the largest group of fungus-derived and lipophilic statins, and of all the statins, only simvastatin use resulted in increased AD risk."

But they say the reason for the difference between simvastatin and the other statins is not clear.  They suggest possible explanations, including simvastatin being a prodrug, with hepatic activation, or its high blood–brain penetrability compared with other statins, or different levels of lipid control.

However, they conclude that many questions remain, and until they are answered both fungus-derived and synthetic statins should be used for the prevention of cardiovascular and cerebrovascular outcomes.

To Medscape Medical News, Dr Yasar added: "The researchers did a sensitivity analysis excluding switchers on the fungus-derived vs synthetic statin comparison and the effect became nonsignificant, but they didn't appear to do the same analysis on the lipophilic-hydrophilic comparison. It would be interesting to look at this further."

She added: "I don't think we can definitely say that any type of statin is better or worse than any other from this study.  It would have been good to have a nonstatin comparison group to get some information on whether statins per se are associated with a protective effect. Perhaps a future study could include a group of patients taking nonstatin lipid lowering drugs —  that would be the best comparator group."

"Based on the data we have, we should select a statin based on its ability to reduce stroke and MI [myocardial infarction]," she said. "We have conflicting data on their effect on cognition and Alzheimer's, and I don't think we have enough evidence to select or reject any particular statin for Alzheimer's risk."   

The study was funded by the Alzheimer's Society of Canada. Dr Brassard has disclosed no relevant financial relationships. 

Neurology. Published online December 15. Abstract, Editorial

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